Substituted cyclic compounds, preparation method and pharmaceutical compositions containing them

ABSTRACT

The invention concerns compounds of formula (1): R-A-R′ wherein: A is as defined in the description; R represent a group (V), (VI), (VII), or (VIII), where E, Q, R 1 , R 2 , R 3 , v and R 4  are as defined in the description; R′ represents a —(CH 2 ) t —R 5  group wherein t and R 5  are as defined in the description, and medicaments containing the same

FIELD OF THE INVENTION

The present invention relates to new substituted cyclic compounds havingvery valuable pharmacological characteristics in respect ofmelatoninergic receptors.

DESCRIPTION OF THE PRIOR ART

The prior art discloses retroamide chain indoles substituted by amidesor carbamates for use as antagonists of GnRH (WO 9721707) and amidechain indoles substituted by amides, carbamates or ureas for use asantihypertensive agents (U.S. Pat. No. 4,803,218).

Retroamide chain benzofuran and benzothiophene compounds substituted byamides or carbamates have also been described as anti-inflammatoryagents (EP 685475) or inhibitors of bone resorption.

BACKGROUND OF THE INVENTION

In the last ten years, numerous studies have demonstrated the major roleplayed by melatonin (5-methoxy-N-acetyltryptamine) in numerousphysiopathological phenomena and also in the control of circadianrhythm. Its half-life is, however, quite short owing to its beingrapidly metabolised. It is thus very useful to be able to provide theclinician with melatonin analogues that are metabolically more stableand that have an agonist or antagonist character on the basis of which atherapeutic effect that is superior to that of the hormone itself may beexpected.

In addition to their beneficial action on disorders of circadian rhythm(J. Neurosurg. 1985, 63, pp 321–341) and sleep disorders(Psychopharmacology, 1990, 100, pp 222–226), ligands of themelatoninergic system have valuable pharmacological properties inrespect of the central nervous system, especially anxiolytic andantipsychotic properties (Neuropharmacology of Pineal Secretions, 1990,8 (3–4), pp 264–272) and analgesic properties (Pharmacopsychiat., 1987,20, pp 222–223), and also for the treatment of Parkinson's disease (J.Neurosurg. 1985, 63, pp 321–341) and Alzheimer's disease (BrainResearch, 1990, 528, pp 170–174). Those compounds have also shownactivity on certain cancers (Melatonin—Clinical Perspectives, OxfordUniversity Press, 1988, pp 164–165), ovulation (Science 1987, 227, pp714–720), diabetes (Clinical Endocrinology, 1986, 24, pp 359–364), andin the treatment of obesity (International Journal of Eating Disorders,1996, 20 (4), pp 443–446).

Those various effects take place via the intermediary of specificmelatonin receptors. Molecular biology studies have shown the existenceof a number of receptor sub-types that can bind the hormone (TrendsPharmacol. Sci., 1995, 16, p 50; WO 97.04094). It has been possible tolocate some of those receptors and to characterise them for differentspecies, including mammals. In order to be able to understand thephysiological functions of those receptors better, it is very valuableto have specific ligands available. Moreover, by interacting selectivelywith one or other of those receptors, such compounds can be excellentmedicaments for the clinician in the treatment of pathologies associatedwith the melatoninergic system, some of which have been mentioned above.

In addition to the fact that the compounds of the present invention arenew, they exhibit very great affinity for melatonin receptors and/orselectivity for one or other of the melatoninergic receptor sub-types.

DETAILED DESCRIPTION OF THE INVENTION

More specifically, the present invention relates to compounds of formula(I):R-A-R′  (I)

wherein

-   ♦ A represents    -   a ring system of formula (II):

-   -    wherein        -   X represents an oxygen, sulphur or nitrogen atom or a group            C(H)_(q) (wherein q is 0, 1 or 2) or NR₀ (wherein R₀            represents a hydrogen atom, a linear or branched            (C₁–C₆)alkyl group, an aryl group, an aryl-(C₁–C₆)alkyl            group in which the alkyl moiety is linear or branched, or            SO₂Ph),        -   Y represents a nitrogen atom or a group C(H)_(q) (wherein q            is 0, 1 or 2),        -   Z represents a nitrogen atom or a group C(H)_(q) (wherein q            is 0, 1 or 2), but X, Y and Z cannot represent three hetero            atoms simultaneously,        -   B represents a benzene or pyridine nucleus,        -   the symbol            means that the bonds may be single or double, it being            understood that the valency of the atoms is respected.    -   wherein R substitutes the ring B and R′ substitutes the ring        containing the groups X, Y and Z, or R and R′ substitute the        ring B,    -   a ring system of formula (III):

-   -    wherein        -   X′ represents an oxygen or sulphur atom or a group C(H)_(q)            (wherein q is 0, 1 or 2),        -   Y′ represents a group C(H)_(q) (wherein q is 0, 1 or 2) or            NR₀ wherein R₀ is as defined hereinbefore,        -   Z′ represents a group C(H)_(q) (wherein q is 0, 1 or 2) or            NR₀ wherein R₀ is as defined hereinbefore,        -   T′ represents an oxygen or sulphur atom or a group C(H)_(q)            (wherein q is 0, 1 or 2),    -    it being understood that, when Y′ or Z′ represents a hetero        atom, the other three variables ((X′, Z′, T′) and (X′, Y′, T′),        respectively) cannot represent a hetero atom,        -   the symbol            is as defined hereinbefore,        -   B′ represents:            -   a benzene nucleus            -   a naphthalene nucleus when X′, Y′, Z′ and T′ do not                simultaneously represent a group C(H)_(q) (wherein q is                0, 1 or 2),            -   or a pyridine nucleus when X′ and T′ simultaneously                represent a group C(H)_(q) (wherein q is 0, 1 or 2),    -    wherein R substitutes the ring B′ and R′ substitutes the ring        containing the groups X′, Y′, Z′ and T′, or R and R′ substitute        the ring B′,    -   a ring system of formula (IV):

-   -   representing the ring systems (IV_(a-d)):

-   -    wherein        -   n is an integer such that 0≦n≦3,        -   W represents an oxygen, sulphur or nitrogen atom, or a group            [C(H)_(q)]_(p) (wherein q is 0, 1 or 2, and p is 1 or 2) or            NR₀ wherein R₀ is as defined hereinbefore,        -   the symbol            is as defined hereinbefore,            wherein R′ substitutes the ring

and R substitutes one or other of the two other rings,

-   -   or a biphenyl group wherein R substitutes one of the benzene        rings and R′ substitutes the other, or R and R′ substitute the        same benzene ring,    -    it being understood that the ring systems of formulae        (II), (III) and (IV) and the biphenyl group may be unsubstituted        or substituted (in addition to the substituents R and R′) by        from 1 to 6 radicals, which may be the same or different,        selected from R_(a), OR_(a), COR_(a), COOR_(a), OCOR_(a),        OSO₂CF₃ and halogen atoms,    -    wherein R_(a) represents a hydrogen atom, an unsubstituted or        substituted linear or branched (C₁–C₆)alkyl group, an        unsubstituted or substituted linear or branched (C₂–C₆)alkenyl        group, an unsubstituted or substituted linear or branched        (C₂–C₆)alkynyl group, a linear or branched (C₁–C₆)polyhaloalkyl        group, an unsubstituted or substituted (C₃–C₈)cycloalkyl group,        an unsubstituted or substituted (C₃–C₈)cycloalkyl-(C₁–C₆)alkyl        group in which the alkyl group is linear or branched, an        unsubstituted or substituted (C₃–C₈)cycloalkenyl group, an        unsubstituted or substituted (C₃–C₈)cycloalkenyl-(C₁–C₆)alkyl        group in which the alkyl group is linear or branched, an aryl        group, an aryl-(C₁–C₆)alkyl group in which the alkyl moiety is        linear or branched, an aryl-(C₁–C₆)alkenyl group in which the        alkenyl moiety is linear or branched, a heteroaryl group, a        heteroaryl-(C₁–C₆)alkyl group in which the alkyl moiety is        linear or branched, a heteroaryl-(C₁–C₆)alkenyl group in which        the alkenyl moiety is linear or branched, an unsubstituted or        substituted linear or branched (C₁–C₆)heterocycloalkyl group, an        unsubstituted or substituted heterocycloalkenyl group, a        substituted or unsubstituted heterocycloalkyl-(C₁–C₆)alkyl group        in which the alkyl moiety is linear or branched, or a        substituted or unsubstituted heterocycloalkenyl-(C₁–C₆)alkyl        group in which the alkyl moiety is linear or branched,

-   ♦ R represents:    -   a group of formula (V):

-   -    wherein        -   Q represents a sulphur or oxygen atom,        -   R′ represents a group NR′_(a)R″_(a) or OR¹ _(a) (wherein            R′_(a) and R″_(a), which may be the same or different, may            take any of the values of R_(a) and may also form, together            with the nitrogen atom carrying them, a 5- to 10-membered            cyclic group which may contain, in addition to the nitrogen            atom by which it is linked, from one to three hetero atoms            selected from oxygen, sulphur and nitrogen, and R¹ _(a) may            take any of the values of R_(a) except for the hydrogen            atom),    -   a group of formula (VI):

-   -    wherein        -   R² represents a group R_(a) as defined hereinbefore,        -   R³ represents a group COR′_(a), CSR′_(a), CONR′_(a)R″_(a),            CSNR′_(a)R″_(a), COOR′_(a), CSOR′_(a) or S(O)_(v)R′_(a)            (wherein R′_(a) and R″_(a), which may be the same or            different, are as defined hereinbefore and may also form,            together with the nitrogen atom carrying them, a cyclic            group as defined hereinbefore, and v is 1 or 2),    -   a group of formula (VII):

-   -    wherein v is as defined hereinbefore and R⁴ represents a group        NR′_(a)R″_(a), NR_(a)COR′_(a), NR_(a)CSR′_(a),        NR_(a)CONR′_(a)R″_(a), NR_(a)CSNR′_(a)R″_(a) or NR_(a)COOR′_(a),        wherein R_(a), R′_(a) and R″_(a) are as defined hereinbefore,    -   or, when A represents a ring system of formula (II) or (III) or        a biphenyl group, forms, together with two adjacent carbon atoms        of the ring structure A carrying it,    -   a ring of formula (VIII):

-   -   the ring formed containing from 5 to 7 atoms and it being        possible for the said ring to contain from 1 to 3 hetero atoms        selected from nitrogen, sulphur and oxygen, and one or more        unsaturations, and being optionally substituted by one or more        radicals, which may be the same or different, selected from        R_(a), OR_(a), COR_(a), COOR_(a), OCOR_(a), NR′_(a)R′_(a),        NR_(a)COR′_(a), CONR′_(a)R″_(a), cyano, oxo, SR_(a), S(O)R_(a),        SO₂R_(a), CSR_(a), NR_(a)CSR′_(a), CSNR′_(a)R″_(a),        NR_(a)CONR′_(a)R″_(a), NR_(a)CSNR′_(a)R″_(a) and halogen atoms,    -   wherein R_(a), R′_(a) and R″_(a), which may be the same or        different, are as defined hereinbefore and R′_(a) and R″_(a) may        also form, together with the nitrogen atom carrying them, a        cyclic group as defined hereinbefore,

-   ♦ and R′ represents a group of formula (IX):    -G-R⁵  (IX)    -    wherein        -   G represents an alkylene chain —(CH₂)_(t)— (wherein t is an            integer such that 0≦t≦4 when A represents a tricyclic            structure and such that 1≦t≦4 when A represents a bicyclic            structure), optionally substituted by one or more radicals,            which may be the same or different, selected from R_(a),            OR_(a), COOR_(a), COR_(a) (in which R_(a) is as defined            hereinbefore) or halogen atoms,        -   and R⁵ represents a group

wherein Q, R_(a), R′_(a) and R″_(a) (which may be the same or different)are as defined hereinbefore, it being possible for R′_(a) and R″_(a) toform, together with the nitrogen atom carrying them, a cyclic group asdefined hereinbefore,it being understood that:

-   -   “heterocycloalkyl” is taken to mean any saturated mono- or        poly-cyclic group containing from 5 to 10 atoms containing from        1 to 3 hetero atoms selected from nitrogen, oxygen and sulphur,    -   “heterocycloalkenyl” is taken to mean any non-aromatic mono- or        poly-cyclic group containing one or more unsaturations,        containing from 5 to 10 atoms and which may contain from 1 to 3        hetero atoms selected from nitrogen, oxygen and sulphur,    -   the term “substituted” used in respect of the expressions        “alkyl”, “alkenyl” and “alkynyl” indicates that the groups in        question are substituted by one or more radicals, which may be        the same or different, selected from hydroxy, linear or branched        (C₁–C₆)alkoxy, linear or branched (C₁–C₆)alkyl, linear or        branched (C₁–C₆)polyhaloalkyl, amino and halogen atoms,    -   the term “substituted” used in respect of the expressions        “cycloalkyl”, “cycloalkylalkyl”, “cycloalkenyl”,        “cycloalkenylalkyl”, “heterocycloalkyl”, “heterocycloalkenyl”,        “heterocycloalkylalkyl” and “heterocycloalkenylalkyl” indicates        that the cyclic moiety of the groups in question is substituted        by one or more radicals, which may be the same or different,        selected from hydroxy, linear or branched (C₁–C₆)alkoxy, linear        or branched (C₁–C₆)alkyl, linear or branched        (C₁–C₆)polyhaloalkyl, amino and halogen atoms,    -   “aryl” is taken to mean any aromatic, mono- or poly-cyclic group        containing from 6 to 22 carbon atoms, and also the biphenyl        group,    -   “heteroaryl” is taken to mean any aromatic mono- or poly-cyclic        group containing from 5 to 10 atoms containing from 1 to 3        hetero atoms selected from nitrogen, oxygen and sulphur,    -   it being possible for the “aryl” and “heteroaryl” groups to be        substituted by one or more radicals, which may be the same or        different, selected from hydroxy, linear or branched        (C₁–C₆)alkoxy, linear or branched (C₁–C₆)alkyl, linear or        branched (C₁–C₆)polyhaloalkyl, cyano, carboxy, nitro, amino and        halogen atoms,        it being understood that:    -   when A represents an indole nucleus, there cannot be any        substituents in the 2-position,    -   when A represents an indole nucleus and R represents a group        —NHCOR′_(a), —NHCOOR′_(a) or NHCONR′_(a)R″_(a), then G-R⁵ cannot        represent a group —(CH₂)₂—NHCOR_(b) wherein R_(b) represents a        (C₁–C₄)alkyl or CF₃ group,    -   when A represents a benzofuran or benzothiophene nucleus, there        cannot be any COPh groups (wherein Ph is substituted or        unsubstituted) in the 2-position,    -   when A represents a benzofuran or benzothiophene nucleus, R        cannot represent a group —NR_(a)COR_(c), —NHSO₂R_(c),        —NHCOCH₂R_(c) or NHCONHR_(c) wherein R_(c) represents a        heterocyclic or aryl group,    -   when A represents a tetrahydronaphthalene group, R⁵ cannot        represent a group CONR′_(a)R″_(a),    -   when A represents a hydrocarbon ring system and R⁵ represents a        group NHCOR′_(a), then R cannot represent a group COOR′_(a),    -   the compound of formula (I) cannot represent:

-   N-{8-[(acetylamino)methyl]-2-naphthyl}-2-methylpropanamide,

-   N-(2-{5-[(4-ethoxyanilino)sulphonyl]-1H-indol-3-yl}ethyl)acetamide,

-   8-[(acetylamino)methyl]-N-isopropyl-2-naphthamide,    their enantiomers and diastereoisomers, and addition salts thereof    with a pharmaceutically acceptable acid or base.

Among the pharmaceutically acceptable acids there may mentioned, withoutimplying any limitation, hydrochloric acid, hydrobromic acid, sulphuricacid, phosphonic acid, acetic acid, trifluoroacetic acid, lactic acid,pyruvic acid, malonic acid, succinic acid, glutaric acid, fumaric acid,tartaric acid, maleic acid, citric acid, ascorbic acid, methanesulphonicacid, camphoric acid, oxalic acid etc.

Among the pharmaceutically acceptable bases there may mentioned, withoutimplying any limitation, sodium hydroxide, potassium hydroxide,triethylamine, tert-butylamine etc.

Preferred compounds of the invention are those wherein A represents aring system of formula (II′):

wherein B, X and the symbol

are as defined hereinbefore, or (III′):

wherein B′, T′, X′ and the symbol

are as defined hereinbefore.

The invention advantageously relates to compounds wherein A(unsubstituted or substituted by a single substituent (in addition to Rand R′) preferably in the 2-position (formula II′) or in the 3-position(formula III′), represents a cyclic system of formula (II′):

wherein B, X and the symbol

are as defined hereinbefore, such as, for example,(dihydro)benzothiophene, (dihydro)benzofuran, indole, indoline, indan,indene, azaindole, thienopyridine or furopyridine, or of formula (III′):

wherein B′, T′, X′ and the symbol

are as defined hereinbefore, such as, for example, naphthalene,tetrahydronaphthalene, (thio)chroman, (dihydro)benzodioxin,(dihydro)benzoxathiin, (dihydro)benzochromene.

Even more advantageously, the invention relates to compounds wherein Aof formula (II′) or (III′) is substituted by R in the 5-position(formula II′) or 7-position (formula III′) and by R′ in the 3-position(formula II′) or 1- or 2-position (formula III′).

Preferred substituents R of the invention are those represented by agroup of formula (V), (VI) or (VII).

More advantageously, preferred substituents R of the invention are thoserepresented by a group of formula (V) wherein Q represents an oxygenatom and R¹ represents a group NR′_(a)R″_(a) (wherein R′_(a) and R″_(a)are as defined hereinbefore) or OR¹ _(a) (wherein R¹ _(a) is as definedhereinbefore),

a group of formula (VI) wherein R³ represents a group COR′_(a) orCOOR′_(a) (wherein R′_(a) is as defined hereinbefore),

or a group of formula (VII) wherein v is 2 and R⁴ represents a groupNR′_(a)R″_(a) as defined hereinbefore.

Even more advantageously, preferred substituents R of the invention arethose represented by a group CONR′_(a)R″_(a) or SO₂NR′_(a)R″_(a) whereinR′_(a) and R″_(a), which may be the same or different, represent ahydrogen atom or an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloalkylalkyl, cycloalkenylalkyl, aryl, arylalkyl,heteroaryl or heteroarylalkyl group, such as, for example, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl,phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl,ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl,or form, together with the nitrogen atom carrying them, a piperazine,piperidine, morpholine or thiomorpholine group, or by a group NCOR′_(a),NCOOR′_(a) or COOR¹ _(a) wherein R′_(a) represents a hydrogen atom, analkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl or heteroarylalkyl group, such as, for example, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl,phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl,ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl,and R¹ _(a) represents an alkyl, polyhaloalkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, suchas, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl,allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl,ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl.

Preferred substituents R′ of the invention are those wherein Grepresents an unsubstituted or substituted alkylene chain —(CH₂)_(t)—,wherein t is 2 or 3, and R⁵ represents a group

wherein R_(a), R′_(a), R″_(a) and Q are as defined hereinbefore.

Even more advantageously, preferred substituents R′ of the invention arethose wherein G represents a group —(CH₂)_(t)—, wherein t is 2 or 3, andR⁵ represents a group

wherein R′_(a) represents an alkyl, polyhaloalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl, aryl,arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl,propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl,ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl,or G represents a group —(CH₂)₃— and R⁵ represents a group

wherein R_(a) represents an alkyl, polyhaloalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl, aryl,arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl,propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl,ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl.

More especially, preferred compounds of the invention are those whereinA represents a ring system of formula (II′) or (III′) and R represents agroup of formula (V), (VI) or (VII).

More advantageously, the invention relates to compounds wherein:

A represents a group of formula (II′) or (III′) substituted in the5-position (formula II′) or 7-position (formula III′) by R and in the3-position (formula II′) or 1- or 2-position (formula III′) by R′,

and R represents a group CONR′_(a)R″_(a), SO₂NR′_(a)R″_(a), COOR¹ _(a),NHCOR′_(a) or NHCOOR′_(a) (wherein R′_(a), R¹ _(a) and R′_(a) are asdefined hereinbefore).

Even more advantageously, preferred compounds of the invention are thosewherein A represents a ring system of formula (II′) or (III′) optionallysubstituted (in addition to R and R′) by a substituent in the 2-position(formula II′) or 3-position (formula III′),

substituted in the 5-position (formula II′) or 7-position (formula III′)by R and in the 3-position (formula II′) or 1- or 2-position (formulaIII′) by R′,

R represents a group CONR′_(a)R″_(a), SO₂NR′_(a)R″_(a), COOR′_(a),NHCOR′_(a) or NHCOOR′_(a) (wherein R′_(a), R″_(a) and R¹ _(a) are asdefined hereinbefore),

and R′ is such that G represents an unsubstituted or substitutedalkylene chain —(CH₂)_(t)—, wherein t is 2 or 3, and R⁵ represents agroup

wherein R_(a), R′_(a), R″_(a) and Q are as defined hereinbefore.

Even more especially, the invention relates to (dihydro)benzothiophenes,(dihydro)benzofurans, indoles, indolines, indenes, indans, azaindoles,thieno- or furopyridines optionally substituted in the 2-position, andto dihydronaphthalenes, tetrahydronaphthalenes, naphthalenes or chromansoptionally substituted in the 3-position,

substituted in the 5-position (or 7-position, respectively) by a groupCONR′_(a)R″_(a), SO₂NR′_(a)R″_(a), COOR¹ _(a), NHCOR′_(a) or NHCOOR′_(a)wherein R′_(a) and R′_(a), which may be the same or different, representa hydrogen atom, an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl, aryl, arylalkyl,heteroaryl or heteroarylalkyl group, such as, for example, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl,phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl,ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl,or R′_(a) and R″_(a) form, together with the nitrogen atom carryingthem, a piperazine, piperidine, morpholine or thiomorpholine group, andR¹ _(a) represents an alkyl, polyhaloalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl, aryl,arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl,propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl,ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl,

and substituted in the 3-position (or 1- or 2-position, respectively) bya group —(CH₂)_(t)—NHCOR′_(a) wherein t is 2 or 3 and R′_(a) representsan alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl,cycloakylalkyl, cycloalkenylalkyl, aryl, arylalkyl, heteroaryl orheteroarylalkyl group, such as, for example, methyl, ethyl, propyl,isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl,hexyl, trifluoromethyl, vinyl, allyl, propargyl, phenyl, naphthyl,benzyl, phenethyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,cyclohexenyl, methylcyclopropyl, ethylcyclopropyl, furyl, thienyl,pyridyl, furylmethyl, pyridylmethyl.

Even more advantageously, preferred compounds of the invention are:

naphthalenes, dihydronaphthalenes or tetrahydronaphthalenes optionallysubstituted in the 3-postion, substituted in the 7-position by a groupNHCOR_(a), NHCOOR_(a), CONHR_(a) or COOR¹ _(a) (wherein R_(a) and R¹_(a) are as defined hereinbefore) and substituted in the 1-position by agroup —(CH₂)_(t)—NHCOR′_(a) wherein t is 2 or 3 and R′_(a) is as definedhereinbefore,

or benzofurans or benzothiophenes optionally substituted in the2-position, substituted in the 5-postion by a group NHCOR_(a),NHCOOR_(a), CONHR_(a) or COOR¹ _(a) (wherein R_(a) and R¹ _(a) are asdefined hereinbefore) and substituted in the 3-position by a group—(CH₂)_(t)—NHCOR′_(a) wherein t is 2 or 3 and R′_(a) is as definedhereinbefore.

The invention relates very particularly to the compounds of formula (I)that are

-   N-{2-[6-(acetylamino)-2,3-dihydro-1H-1-indenyl]ethyl}acetamide,-   methyl 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxylate,-   methyl    3-{2-[(cyclopentylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxylate,-   methyl    3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxylate,-   methyl 3-[2-(3-butenoylamino)ethyl]-1-benzofuran-5-carboxylate,-   N,N-diphenyl-3-[3-(acetylamino)propyl]benzo[b]furan-5-carboxamide,-   3-[2-(acetylamino)ethyl]-1-benzofuran-5-carboxamide,-   3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxamide,-   3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxamide,-   3-{2-[(cyclopropylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxamide,-   3-[2-(acetylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide,-   3-{2-[(cyclopentylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxamide,-   3-[2-(benzoylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide,-   3-{2-[(cyclopropylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxamide,-   3-[2-(benzoylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide,-   3-[2-(acetylamino)ethyl]-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,-   N-isopropyl-N-(2-propynyl)-3-[(acetylamino)methyl]-2-benzylbenzo[b]thiophene-5-carboxamide,-   N-{3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl}-2,2,2-trifluoroacetamide,-   N-{2-[5-(acetylamino)-1-benzofuran-3-yl]ethyl}cyclopropanecarboxamide,-   N-{2-[5-(acetylamino)-1-benzothiophen-3-yl]ethyl}benzamide,-   N-{8-[2-([2-phenylacetyl]amino)ethyl]-2-naphthyl}butanamide,-   N-(8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthyl)-1-cyclohexanecarboxamide,-   N-{8-[2-(heptanoylamino)ethyl]-2,6-dinaphthyl}-2-butenamide,-   N-{8-[2-(acetylamino)ethyl]-2-naphthyl}acetamide,-   N-ethyl-8-{2-[(2-phenylacetyl)amino]ethyl}-2-naphthamide,-   N,N-diethyl-8-{2-[2-[(cyclopropylmethyl)amino]-2-oxoethyl}-2-naphthamide,-   N-phenyl-8-(2-{methyl[(propylamino)carbonyl]amino}ethyl)-2-naphthamide,-   N-benzyl-1-{2-[(2,2,2-trifluoroacetyl)amino]ethyl}-2-naphthamide,-   N-(2-{7-[(methylamino)carbonyl]-1-naphthyl}ethyl)-2-furamide,-   N-{2-[7-(aminosulphonyl)-1-naphthyl]ethyl}acetamide,-   N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethyl)acetamide,-   N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethyl)-2-furamide,-   N-(2-{7-[(ethylamino)sulphonyl]-1-naphthyl}ethyl)benzamide,-   N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethyl)cyclopropanecarboxamide,-   N-(3-{5-[(methylamino)sulphonyl]-1-benzofuran-3-yl}propyl)acetamide,-   N-(2-{5-[(propylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)acetamide,-   N-(2-{5-[(cyclopropylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)benzamide,-   N-(2-{5-[(methylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)-2-furamide,-   N-(2-{5-[(methylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)cyclopropanecarboxamide,-   N-(2-{2-benzyl-5-[(methylamino)sulphonyl]-1-benzothiophen-3-yl}ethyl)acetamide,-   N-(2-{5-[(isopropylamino)sulphonyl]-1-benzothiophen-3-yl}ethyl)cyclopropane-carboxamide,-   N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)acetamide,-   N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)cyclopropane-carboxamide,-   N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)benzamide,-   N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)-2-furamide,-   methyl N-{3-[2-(acetylamino)ethyl]benzo[b]furan-5-yl}carbamate,-   methyl    3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-yl-carbamate,-   tert-butyl 3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-carbamate,-   tert-butyl    3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-(methyl)carbamate,-   methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-yl-carbamate,-   methyl 3-[2-(isobutyrylamino)ethyl]-1-benzofuran-5-yl-carbamate,-   methyl    5-[(acetylamino)methyl]-2,3-dihydro-1,4-benzodioxin-6-yl-carbamate,-   methyl    3-[(acetylamino)methyl]-3,4-dihydro-2H-chromen-6-yl-carbamate,-   ethyl 3-[2-(acetylamino)ethyl]-2,3-dihydro-1H-inden-5-yl-carbamate,-   methyl    3-[2-(acetylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate,-   methyl    3-[2-(2-furoylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate,-   methyl    3-[2-(benzoylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate,-   methyl    3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate,-   ethyl N-(8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthyl)carbamate,-   methyl N-{8-[2-(acetylamino)ethyl]-6-phenyl-2-naphthyl}carbamate,-   hexyl    N-{8-[2-(acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}carbamate,-   methyl 8-[2-(acetylamino)ethyl]-2-naphthyl-carbamate,-   methyl 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-yl-carbamate,-   methyl    3-{2-[(cyclopentylcarbonyl)amino]ethyl}-1-benzofuran-5-yl-carbamate,-   methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxylate,-   methyl 3-[2-(isobutylamino)ethyl]-1-benzofuran-5-carboxylate,-   3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxamide.

The enantiomers and diastereoisomers, as well as the addition salts witha pharmaceutically acceptable acid or base, of the preferred compoundsof the invention form an integral part of the invention.

The invention relates also to a process for the preparation of compoundsof formula (I), which process is characterised in that there is used asstarting material the compound of formula (X)

wherein A and R′ are as defined hereinbefore, which is subjected todemethylation using conventional agents such as HBr, AlCl₃, AlBr₃, BBr₃or Lewis acid/nucleophile binary systems such as AlCl₃/PhCH₂SH, orBBr₃/Me₂S, for example, to obtain the compound of formula (XI):HO-A-R′  (XI)wherein A and R′ are as defined hereinbefore,

-   ♦ which is converted, by means of the action of reagents such as    POCl₃, PCl₅, Ph₃PBr₂, PhPCl₄, HBr or HI, into the corresponding    halogenated compound of formula (XII):    Hal-A-R′  (XII)    wherein A and R′ are as defined hereinbefore and Hal represents a    halogen atom (which compounds of formula (XII) can be obtained by    exchange reactions such as, for example, the treatment of a    chlorinated compound with KF in dimethylformamide to yield the    corresponding fluorinated compound or the treatment of a brominated    compound with KI in the presence of copper salts to yield the    corresponding iodinated compound),    which is treated:    with carbon monoxide and Bu₃SnH, the reaction being catalysed with    palladium(0), to yield the corresponding aldehyde of formula (XIII):

wherein A and R′ are as defined hereinbefore,which compound of formula (XIII) may alternatively be obtained bycustomary lithiation methods starting from the halogenated compound offormula (XII), or via the corresponding vinyl compound (obtainedstarting from the compound of formula (XII) by the action ofvinyltributyltin and tetrakis palladium) subjected to ozonolysis, orfurthermore by direct formylation of the nucleus A, for exampleaccording to a Vilsmeier reaction,which compound of formula (XIII) is subjected to an oxidising agent toobtain the compound of formula (XIV):HOOC-A-R′  (XIV)wherein A and R′ are as defined hereinbefore, which is:

-   either subjected, in the presence of an acid catalyst, to the action    of an alcohol of formula R¹ _(a)OH, wherein R¹ _(a) is as defined    hereinbefore, to yield the compound of formula (I/a), a particular    case of the compounds of formula (I):

wherein A, R¹ _(a) and R′ are as defined hereinbefore,which may be subjected to a thionating agent, such as Lawesson'sreagent, for example, to yield the compound of formula (I/b), aparticular case of the compounds of formula (I):

wherein A, R¹ _(a) and R′ are as defined hereinbefore,

-   or converted, after the action of thionyl chloride and an azide, and    then of an acid, into the compound of formula (XV):    H₂N-A-R′  (XV)    wherein A and R′ are as defined hereinbefore, with which there is    condensed:    -   either an acyl chloride ClCOR_(a) or the corresponding anhydride        (mixed or symmetrical), wherein R_(a) is as defined        hereinbefore, to yield the compound of formula (I/c), a        particular case of the compounds of formula (I):

wherein R_(a), A and R′ are as defined hereinbefore,which may be subjected to the action of a compound of formula (XVI):R¹ _(a)-J  (XVI)wherein R¹ _(a) is as defined hereinbefore and J represents a leavinggroup such as a halogen atom or a tosyl group,to obtain the compound of formula (I/d), a particular case of thecompounds of formula (I):

wherein R_(a), R¹ _(a), A and R′ are as defined hereinbefore,which compounds of formulae (I/c) and (I/d) constitute the compound offormula (I/e), a particular case of the compounds of formula (I):

wherein R_(a), R′_(a), A and R′ are as defined hereinbefore,which compound of formula (I/e) may be subjected to a thionating agent,such as Lawesson's reagent, for example, to obtain the compound offormula (I/f), a particular case of the compounds of formula (I):

wherein R_(a), R′_(a), A and R′ are as defined hereinbefore,

-   -   or a compound of formula (XVII):        Q=C═N—R′_(a)  (XVII)        wherein Q and R′_(a) are as defined hereinbefore,        to yield the compound of formula (I/g), a particular case of the        compounds of formula (I):

wherein R′_(a), Q, A and R′ are as defined hereinbefore,which may be subjected to the action of a compound of formula (XVI) toobtain the compound of formula (I/h), a particular case of the compoundsof formula (I):

wherein Q, R¹ _(a), A and R′ are as defined hereinbefore and R² _(a) andR′² _(a), which may be the same or different, may take any of the valuesof R_(a) except for the hydrogen atom and cannot form a cyclic structuretogether with the nitrogen atom carrying them,

-   -   or a compound of formula (XVIII):

wherein R′_(a) is as defined hereinbefore, or its correspondinganhydride (R′_(a)OCO)₂O,to obtain the compound of formula (I/i), a particular case of thecompounds of formula (I):

wherein R′_(a), A et R′ are as defined hereinbefore,which may be subjected to the action of a compound of formula (XVI)and/or the action of a thionating agent to yield the compound of formula(I/j), a particular case of the compounds of formula (I):

wherein R_(a), R′_(a), Q, A and R′ are as defined hereinbefore,

-   -   or a compound of formula (XIX):        R_(a)SO₂Cl  (XIX)        wherein R_(a) is as defined hereinbefore,        optionally followed by the action of a compound of formula (XVI)        to yield the compound of formula (I/k), a particular case of the        compounds of formula (I):

wherein R_(a), A and R′ are as defined hereinbefore,

-   ♦ or which compound of formula (XI) is converted, by means of the    action of benzylthiol and trifluoromethanesulphonic acid, into the    corresponding benzylthio compound of formula (XX):    Ph-CH₂—S-A-R′  (XX)    wherein A and R′ are as defined hereinbefore,    which is placed in the presence of iodosobenzene and hydrochloric    acid to yield the compound of formula (XXI):    ClSO₂-A-R′  (XXI)    wherein A and R′ are as defined hereinbefore, with which there is    condensed an amine R′_(a)R″_(a)NH (wherein R′_(a) and R″_(a) are as    defined hereinbefore),    to obtain the compound of formula (I/l), a particular case of the    compounds of formula (I):    R′_(a)R″_(a)NSO₂-A-R′  (I/l)

wherein R′_(a), R″_(a), A and R′ are as defined hereinbefore,

it being possible for the compound of formula (I/la), a particular caseof the compounds of formula (I/l):H₂NSO₂-A-R′  (I/la)wherein A and R′ are as defined hereinbefore, to be subjected to theaction

-   of an acyl chloride ClCOR′_(a), optionally followed by the action of    a compound of formula (XVI) and/or Lawesson's reagent,    to yield the compound of formula (I/m), a particular case of the    compounds of formula (I):

wherein R_(a), R′_(a), Q, A and R′ are as defined hereinbefore,

-   of a compound of formula (XVII), optionally followed by the action    of a compound of formula (XVI) to obtain the compound of formula    (I/n), a particular case of the compounds of formula (I):

wherein R_(a), R′_(a), R″_(a), Q, A and R′ are as defined hereinbefore,

-   or of a compound of formula (XVIII), optionally followed by the    action of a compound of formula (XVI),    to yield the compound of formula (I/o), a particular case of the    compounds of formula (I):

wherein R_(a), R′_(a), A and R′ are as defined hereinbefore,which compounds (I/a) to (I/o) can be purified in accordance with aconventional separation technique, are converted, if desired, into theiraddition salts with a pharmaceutically acceptable acid or base and,optionally, are separated into their isomers in accordance with aconventional separation technique.

The starting compounds (X) are either commercially available or aredescribed in the literature, for example in the Patent ApplicationsEP0447285, EP0527687, EP0562956, EP0591057, EP0662471, EP0745586,EP0709371, EP0745583, EP0721938, EP0745584, EP0737670, EP0737685, orW09738682.

Another advantageous process of the invention relating to preparation ofthe compounds of formula (I) is characterised in that there is used asstarting material the compound of formula (XXII):

wherein R and the symbol

are as defined hereinbefore, Y″ represents a group C(H)_(q) (wherein qis 0, 1 or 2) or a bond, and X″ represents an oxygen, nitrogen orsulphur atom or a group C(H)_(q) (wherein q is 0, 1 or 2) or NR₀(wherein R₀ is as defined hereinbefore), it being understood that whenX″ represents a nitrogen atom or a group NR₀ then Y″ represents a bond,which is subjected to a Wittig reaction and then to reduction to yieldthe compound of formula (XXIII):

wherein R, X″, Y″, G and the symbol

are as defined hereinbefore,which may be oxidised to yield the compound of formula (XXIV):

wherein R¹, X″, Y″, G and the symbol

are as defined hereinbefore,

which is:

-   either hydrolysed in an acid or basic medium and then subjected,    after activation to the acid chloride form or in the presence of a    coupling agent, to the action of an amine HNR′_(a)R″_(a) wherein    R′_(a) and R″_(a) are as defined hereinbefore to yield the compound    of formula (I/p), a particular case of the compounds of formula (I):

wherein R, X″, Y″, G, R′_(a), R″_(a) and the symbol

are as defined hereinbefore,which may be subjected to a thionating agent such as Lawesson's reagentto yield the compound of formula (I/q), a particular case of thecompounds of formula (I):

wherein R, X″, Y″, G, R′_(a), R″_(a) and the symbol

are as defined hereinbefore,

-   or hydrolysed in an acid or basic medium and then converted into the    corresponding azide to yield, after having been subjected to a    Curtius rearrangement and hydrolysis, the compound of formula (XXV):

wherein R, X″, Y″and G are as defined hereinbefore,which is reacted with

-   -   an acyl chloride ClCOR′_(a) or the corresponding anhydride        (mixed or symmetrical) wherein R′_(a) is as defined        hereinbefore, optionally followed by the action of a compound of        formula (XVI) and/or the action of a thionating agent to yield        the compound of formula (I/r), a particular case of the        compounds of formula (I):

wherein R. X″, Y″, G, R_(a), R′_(a), Q and the symbol

are as defined hereinbefore,

-   -   or with a compound of formula (XVII), optionally followed by the        action of a compound of formula (XVI) to yield the compound of        formula (I/s), a particular case of the compounds of formula        (I):

wherein R, X″, Y″, G, R_(a), R′_(a), R″_(a), Q and the symbol

are as defined hereinbefore,which compounds (I/p) to (I/s) can be purified in accordance with aconventional separation technique, are converted, if desired, into theiraddition salts with a pharmaceutically acceptable acid or base and,optionally, are separated into their isomers in accordance with aconventional separation technique.

The compounds of formula (XXII) are either commercially available oreasily accessible to the person skilled in the art,

-   starting from the compound of formula (XXVI):

wherein R is as defined hereinbefore and X′″ represents an oxygen orsulphur atom or a group NR₀ (wherein R₀ is as defined hereinbefore),(the compound of formula (XXVI) either being commercially available orbeing obtained starting from the compound of formula (XXVI′):

wherein X′″ is as defined hereinbefore, by conventional reactions forsubstitution of the aromatic nucleus),

-   -   which is subjected to the action of AlCl₃ to yield the compound        of formula (XXVII):

wherein R and X′″ are as defined hereinbefore,which is subjected to bromination to obtain the compound of formula(XXVIII):

wherein X′″ and R are as defined hereinbefore,which is placed in a basic medium to yield the compound of formula(XXIX), a particular case of the compounds of formula (XXII):

wherein R and X′″ are as defined hereinbefore,

-   or starting from the compound of formula (XXX):

wherein R, X″, Y″ and the symbol

are as defined hereinbefore,which is cyclised in the presence of polyphosphoric acid to yield thecompound of formula (XXII).

The invention relates also to a process for the preparation of compoundsof formula (I) wherein R represents a ring of formula (VIII), whichprocess is characterised in that compounds of formulae (I/a) to (I/s)are used as starting materials, which are cyclised according to methodsdescribed in the literature, for example in the Patent ApplicationsEP0708099 or WO09732871.

The compounds of the invention and pharmaceutical compositionscomprising them are proving to be useful in the treatment of disordersof the melatoninergic system.

Pharmacological study of the compounds of the invention has in factshown them to be non-toxic, to have strong affinity for melatoninreceptors and to possess important activities in respect of the centralnervous system and, in particular, there have been found therapeuticproperties in relation to sleep disorders, anxiolytic, antipsychotic andanalgesic properties and in relation to the microcirculation, enablingit to be established that the products of the invention are useful inthe treatment of stress, sleep disorders, anxiety, seasonal affectivedisorder, cardiovascular pathologies, pathologies of the digestivesystem, insomnia and fatigue resulting from jet lag, schizophrenia,panic attacks, melancholia, appetite disorders, obesity, insomnia,psychotic disorders, epilepsy, diabetes, Parkinson's disease, seniledementia, various disorders associated with normal or pathologicalageing, migraine, memory loss, Alzheimer's disease, and also cerebralcirculation disorders. In another field of activity, it appears that, intreatment, the products of the invention can be used in sexualdysfunction, that they have ovulation-inhibiting properties andimmunomodulating properties and are able to be used in the treatment ofcancers.

The compounds will preferably be used in the treatment of seasonalaffective disorder, sleep disorders, cardiovascular pathologies,insomnia and fatigue resulting from jet lag, appetite disorders andobesity.

For example, the compounds will be used in the treatment of seasonalaffective disorder and sleep disorders.

The present invention relates also to pharmaceutical compositionscomprising at least one compound of formula (I), alone or in combinationwith one or more pharmaceutically acceptable excipients.

Among the pharmaceutical compositions according to the invention theremay be mentioned more especially those that are suitable for oral,parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocularor respiratory administration and especially tablets, dragees,sublingual tablets, sachets, paquets, gelatin capsules, glossettes,lozenges, suppositories, creams, ointments, dermal gels and drinkable orinjectable ampoules.

The dosage varies according to the sex, age and weight of the patient,the route of administration, the nature of the therapeutic indication,or possible associated treatments, and ranges from 0.01 mg to 1 g per 24hours in 1 or more administrations.

The following Examples illustrate the invention but do not limit it inany way. The following Preparations yield compounds of the invention orsynthesis intermediates that are useful in preparation of the compoundsof the invention.

Preparation 1 N-[2-(7-Hydroxy-1-naphthyl)ethyl]acetamide

Under an inert atmosphere, 27.5 mmol of boron tribromide/dimethylsulphide complex are dissolved in 100 ml of dichloromethane and stirredfor 15 min at ambient temperature. A solution of 13.7 mmol ofN-[2-(7-methoxy-1-naphthyl)ethyl]acetamide in 50 ml of dichloromethaneis added and the reaction mixture is heated at reflux for 30 hours.After cooling, the reaction mixture is hydrolysed with caution and thedichloromethane is evaporated off. The mixture is then extracted withethyl acetate, the combined organic phases are washed with a 1M aqueoussolution of potassium bicarbonate and then with 1M sodium hydroxidesolution. The organic phase is dried over magnesium sulphate andconcentrated to yield the title compound.

Preparation 2 N-[2-(7-Hydroxy-1-naphthyl)ethyl]-2-phenylacetamide

The procedure is as in Preparation 1, but theN-[2-(7-methoxy-1-naphthyl)ethyl]acetamide is replaced byN-[2-(7-methoxy-1-naphthyl)ethyl]-2-phenylacetamide.

In Preparations 3 to 37, the procedure is as in Preparation 1, but theN-[2-(7-methoxy-1-naphthyl)ethyl]acetamide is replaced by theappropriate methoxylated starting substrate.

Preparation 3 N-[2-(7-Hydroxy-1-naphthyl)ethyl]-2-bromoacetamidePreparation 4N-[2-(8-Hexyl-7-hydroxy-1-naphthyl)ethyl]-2-phenylacetamide Preparation5 N-Cyclopropylmethyl-2-(7-hydroxy-1-naphthyl)acetamide Preparation 6N-Cyclohexyl-4-(7-hydroxy-1-naphthyl)butanamide Preparation 7N-[2-(7-Hydroxy-1-naphthyl)ethyl]-N-methyl-N′-propylurea Preparation 8N-[3-(7-Hydroxy-1-naphthyl)propyl]acetamide Preparation 9N-[2-(7-Hydroxy-1-naphthyl)ethyl]-3-butenamide Preparation 10N-[3-(7-Hydroxy-1-naphthyl)propyl]-1-cyclohexanecarboxamide Preparation11 N-[2-(2-Hydroxy-1-naphthyl)ethyl]-2,2,2-trifluoroacetamidePreparation 12 N-[2-(2-Hydroxy-1-naphthyl)-1-methylethyl]propanamidePreparation 13 N-[2-(7-Hydroxy-3-phenyl-1-naphthyl)ethyl]acetamidePreparation 14 N-[2-(3-Benzoyl-7-hydroxy-1-naphthyl)ethyl]-N′-propylureaPreparation 15N-{2-13-(Cyclopropylmethyl)-7-hydroxy-1-naphthyl]ethyl}acetamidePreparation 16 N-[3-(5-Hydroxybenzo[b]furan-3-yl)propyl]acetamidePreparation 17 N-Methyl-4-(5-hydroxybenzo[b]furan-3-yl)butanamidePreparation 18 N-[2-(5-Hydroxybenzo[b]furan-3-yl)ethyl]acetamidePreparation 19N-[(2-Benzyl-5-hydroxybenzo[b]thiophen-3-yl)methyl]acetamide Preparation20 N-[2-(5-Hydroxythieno[3,2-b]pyridin-3-yl)ethyl]acetamide Preparation21 N-[2-(5-Hydroxy-1H-3-indolyl)ethyl]benzamide Preparation 22N-{2-[2-(4-Fluorobenzyl)-5-hydroxy-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]ethyl}acetamidePreparation 23N-[2-(2-Benzyl-5-hydroxybenzo[b]furan-3-yl)ethyl]-1-cyclopropane-carboxamidePreparation 24 N-[(6-Hydroxy-3,4-dihydro-2H-3-chromenyl)methyl]acetamidePreparation 25N-[2-(6-Hydroxy-3,4-dihydro-2H-4-chromenyl)ethyl]-2-phenylacetamidePreparation 26 N-[(6-Hydroxy-2-phenyl-2H-3-chromenyl)methyl]acetamidePreparation 27 N-[(6-Hydroxy-2-phenyl-2H-3-chromenyl)methyl]butanamidePreparation 28N-[2-(6-Hydroxy-3,4-dihydro-2H-4-thiochromenyl)ethyl]acetamidePreparation 29 N-[2-(7-Hydroxy-1,4-benzodioxin-2-yl)ethyl-N′-propylureaPreparation 30N-[2-(7-Hydroxy-2,3-dihydro-1,4-benzodioxin-2-yl)ethyl]acetamidePreparation 31N-[2-(6-Hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]acetamidePreparation 32N-[(9-Hydroxy-2,3-dihydro-1H-benzo[f]chromen-2-yl)methyl]-2-cyclopropylacetamidePreparation 33N-Cyclopropyl-N′-(4-hydroxy-2,3-dihydro-1H-2-phenalenyl)thioureaPreparation 34 N-Cyclobutyl-3-hydroxy-4,5-dihydro-3H-benzo[cd]isobenzofuran-4-carboxamide Preparation 35N-{2-[7-Hydroxy-3-naphthyl-1-naphthyl]ethyl}heptanamide Preparation 36N-[2-(7-Hydroxy-1,2,3,4-tetrahydro-1-naphthyl)ethyl]acetamidePreparation 37 N-[2-(6-Hydroxy-2,3-dihydro-1H-1-indenyl)ethyl]acetamidePreparation 38 N-Cyclohexyl-4-(7-chloro-1-naphthyl)butanamide

Chlorine (10 mmol) is bubbled into dichlorophenylphosphine at a flowrate such that the reaction temperature is maintained between 70 and 80°C. After all the chlorine has been added, the phenylphosphinetetrachloride so obtained is a pale yellow liquid. 10 mmol of theproduct obtained in Preparation 5 are added all at once and the reactionmixture is heated at 160° C. overnight. After cooling, the solution ispoured into a water/ice mixture (20 ml) and is neutralised with a 50%aqueous solution of sodium hydroxide. After extraction with ether, theorganic phases are dried and concentrated under reduced pressure toyield a residue, which is chromatographed on silica gel to obtain thepure title product.

In Preparation 39, the procedure is as in Preparation 38, but theappropriate starting compound is used.

Preparation 39 N-[(6-Chloro-3,4-dihydro-2H-3-chromenyl)methyl]acetamide

Starting compound: Preparation 24

Preparation 40 N-[2-(7-Bromo-1-naphthyl)ethyl]-2-phenylacetamide

Triphenylphosphine (10 mmol) and acetonitrile (70 ml) are poured into a150 ml three-necked flask equipped with a bromine funnel, a condensersurmounted by a tube filled with calcium chloride and a mechanicalstirrer. The solution is cooled with the aid of an ice bath, withstirring, and bromine is added (10 mmol). At the end of the addition,the ice bath is removed and the product obtained in Preparation 2 (8mmol) is then added. The reaction mixture is stirred at 60–70° C. untilthe starting compound has disappeared (monitored by TLC). At the end ofthe reaction, the mixture is filtered and the filtrate is thenconcentrated under reduced pressure. The residue is taken up in ethylacetate, washed with water and then with saturated potassium hydrogencarbonate solution and once again with water, and is then dried overmagnesium sulphate and concentrated under reduced pressure. The residueis filtered through silica gel to yield the title product.

In Preparations 41 to 72.1, the procedure is as in Preparation 40,starting from the appropriate reactant.

Preparation 41 N-Cyclopropylmethyl-2-(7-bromo-1-naphthyl)acetamide

Starting compound: Preparation 5

Preparation 42 N-[2-(7-Bromo-1-naphthyl)ethyl]-N-methyl-N′-propylurea

Starting compound: Preparation 7

Preparation 43 N-[3-(7-Bromo-1-naphthyl)propyl]-1-cyclohexanecarboxamide

Starting compound: Preparation 10

Preparation 44 N-[2-(2-Bromo-1-naphthyl)ethyl]-2,2,2-trifluoroacetamide

Starting compound: Preparation 11

Preparation 45 N-[2-(3-Benzoyl-7-bromo-1-naphthyl)ethyl]-N′-propylurea

Starting compound: Preparation 14

Preparation 46 N-[3-(5-Bromobenzo[b]furan-3-yl)propyl]acetamide

Starting compound: Preparation 16

Preparation 47N-[(2-Benzyl-5-bromobenzo[b]thiophen-3-yI)methyl]acetamide

Starting compound: Preparation 19

Preparation 48N-[2-(5-Bromo-2-(4-fluorobenzyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3yl)ethyl]acetamide

Starting compound: Preparation 22

Preparation 49N-[2-(6-Bromo-3,4-dihydro-2H-4-chromenyl)ethyl]-2-phenylacetamide

Starting compound: Preparation 25

Preparation 50 N-[(6-Bromo-2-phenyl-2H-3-chromenyl)methyl]acetamide

Starting compound: Preparation 26

Preparation 51N-[2-(6-Bromo-3,4-dihydro-2H-4-thiochromenyl)ethyl]acetamide

Starting compound: Preparation 28

Preparation 52 N-[2-(7-Bromo-1,4-benzodioxin-2-yl)ethyl]-N′-propylurea

Starting compound: Preparation 29

Preparation 53N-[2-(6-Bromo-2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]acetamide

Starting compound: Preparation 31

Preparation 54N-[(9-Bromo-2,3-dihydro-1H-benzo[f]chromen-2-yl)methyl]-2-cyclopropylacetamide

Starting compound: Preparation 32

Preparation 55N-(4-Bromo-2,3-dihydro-1H-2-phenalenyl)-N′-cyclopropylthiourea

Starting compound: Preparation 33

Preparation 56 N-Cyclobutyl-6-bromo-4,5-dihydro-3H-benzo[cd]isobenzofuran-4-carboxamide

Starting compound: Preparation 34

Preparation 57

N-[2-(7-Bromo-3-naphthyl-1-naphthyl)ethyl]heptanamide

Starting compound: Preparation 35

Preparation 58 N-[2-(7-Bromo-1-naphthyl)ethyl]acetamide

Starting compound: Preparation 1

Preparation 59 N-[2-(7-Bromo-1-naphthyl)ethyl]-3-butenamide

Starting compound: Preparation 9

Preparation 60 N-[2-(7-Bromo-1-naphthyl)ethyl]-2-bromoacetamide

Starting compound: Preparation 3

Preparation 61 N-[2-(7-Bromo-8-hexyl-1-naphthyl)ethyl]-2-phenylacetamide

Starting compound: Preparation 4

Preparation 62 N-[3-(7-Bromo-1-naphthyl)propyl]acetamide

Starting compound: Preparation 8

Preparation 63 N-[2-(2-Bromo-1-naphthyl)-1-methylethyl]propanamide

Starting compound: Preparation 12

Preparation 64N-{2-[7-Bromo-3-(cyclopropylmethyl)-1-naphthyl]ethyl}acetamide

Starting compound: Preparation 15

Preparation 65 N-Methyl-3-(5-bromobenzo[b]furan-3-yl)butanamide

Starting compound: Preparation 17

Preparation 66 N-[2-(5-Bromothieno[3,2-b]pyridin-3-yl)ethyl]acetamide

Starting compound: Preparation 20

Preparation 67 N-[2-(5-Bromo-1H-3-indolyl)ethyl]benzamide

Starting compound: Preparation 21

Preparation 68

N-[2-(2-Benzyl-5-bromobenzo[b]furan-3-yl)ethyl]-1-cyclopropane-carboxamide

Starting compound: Preparation 23

Preparation 69 N-[(6-Bromo-2-phenyl-2H-3-chromenyl)methyl]butanamide

Starting compound: Preparation 27

Preparation 70 N-[2-(6-Bromo-2,3-dihydro-1H-1-indenyl)ethyl]acetamide

Starting compound: Preparation 37

Preparation 71 N-[2-(7-Bromo-3-phenyl-1-naphthyl)ethyl]acetamide

Starting compound: Preparation 13

Preparation 72 N-[2-(5-Bromobenzo[b]furan-3-yl)ethyl]acetamide

Starting compound: Preparation 18

Preparation 72.1N-[2-7-Bromo-1,2,3,4-tetrahydro-1-naphthyl)ethyl]acetamide

Starting compound: Preparation 36

Preparation 73 N-[2-(7-Iodo-1-naphthyl)ethyl]-2-phenylacetamide

A mixture of the product obtained in Preparation 40 (2 mmol), potassiumiodide (30 mmol) and copper(I) iodide (10 mmol) inhexamethylphosphoramide (6 ml) is heated at 150–160° C., with stirring,under a nitrogen atmosphere until 90% conversion has been achieved(monitored by TLC). Then, dilute hydrochloric acid, and then ether, areadded and the mixture is then filtered to remove the insoluble copper(I)salts. The organic phase is separated off, washed with sodium sulphitesolution and with water, dried over magnesium sulphate and evaporated toyield a residue which is chromatographed on silica gel to yield thetitle product.

In Preparations 74 to 108 the procedure is as in Preparation 73, but theproduct of Preparation 40 is replaced by the appropriate substrate.

Preparation 74 N-Cyclopropylmethyl-2-(7-iodo-1-naphthyl)acetamide

Starting compound: Preparation 41

Preparation 75 N-[2-(7-Iodo-1-naphthyl)ethyl]-N-methyl-N′-propylurea

Starting compound: Preparation 42

Preparation 76 N-[3-(7-Iodo-1-naphthyl)propyl]-1-cyclohexanecarboxamide

Starting compound: Preparation 43

Preparation 77 N-[2-(2-Iodo-1-naphthyl)ethyl]-2,2,2-trifluoroacetamide

Starting compound: Preparation 44

Preparation 78 N-[2-(3-Benzoyl-7-iodo-1-naphthyl)ethyl]-N′-propylurea

Starting compound: Preparation 45

Preparation 79 N-[3-(5-Iodobenzo[b]furan-3-yl)propyl]acetamide

Starting compound: Preparation 46

Preparation 80 N-[(2-Benzyl-5-iodobenzo[b]thiophen-3-yl)methyl]acetamide

Starting compound: Preparation 47

Preparation 81N-[2-(5-Iodo-2-(4-fluorobenzyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethyl]acetamide

Starting compound: Preparation 48

Preparation 82 N-[(6-Iodo-3,4-dihydro-2H-3-chromenyl)methyl]acetamide

Starting compound: Preparation 39

Preparation 83N-[2-(6-Iodo-3,4-dihydro-2H-4-chromenyl)ethyl]-2-phenylacetamide

Starting compound: Preparation 49

Preparation 84 N-[(6-Iodo-2-phenyl-2H-3-chromenyl)methyl]acetamide

Starting compound: Preparation 50

Preparation 85N-[2-(6-Iodo-3,4-dihydro-2H-4-thiochromenyl)ethyl]acetamide

Starting compound: Preparation 51

Preparation 86 N-[2-(7-Iodo-1,4-benzodioxin-2-yl)ethyl]-N′-propylurea

Starting compound: Preparation 52

Preparation 87N-[2-(6-Iodo-2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]acetamide

Starting compound: Preparation 53

Preparation 88N-[(9-Iodo-2,3-dihydro-1H-benzo[f]chromen-2-yl)methyl]-2-cyclopropyl-acetamide

Starting compound: Preparation 54

Preparation 89N-(4-Iodo-2,3-dihydro-1H-2-phenalenyl)-N′-cyclopropylthiourea

Starting compound: Preparation 55

Preparation 90N-Cyclobutyl-6-iodo-4,5-dihydro-3H-benzo[cd]isobenzofuran-4-carboxamide

Starting compound: Preparation 56

Preparation 91 N-[2-(7-Iodo-3-naphthyl-1-naphthyl)ethyl]heptanamide

Starting compound: Preparation 57

Preparation 92 N-[2-(7-Iodo-1-naphthyl)ethyl]acetamide

Starting compound: Preparation 58

Preparation 93 N-[2-(7-Iodo-1-naphthyl)ethyl]-3-butenamide

Starting compound: Preparation 59

Preparation 94 N-[2-(7-Iodo-1-naphthyl)ethyl]-2-bromoacetamide

Starting compound: Preparation 60

Preparation 95 N-[2-(7-Iodo-8-hexyl-1-naphthyl)ethyl]-2-phenylacetamide

Starting compound: Preparation 61

Preparation 96 N-Cyclohexyl-4-(7-iodo-1-naphthyl)butanamide

Starting compound: Preparation 38

Preparation 97 N-[3-(7-Iodo-1-naphthyl)propyl]acetamide

Starting compound: Preparation 62

Preparation 98 N-[2-(2-Iodo-1-naphthyl)-1-methylethyl]propanamide

Starting compound: Preparation 63

Preparation 99N-{2-[7-Iodo-3-(cyclopropylmethyl)-1-naphthyl]ethyl}acetamide

Starting compound: Preparation 64

Preparation 100 N-Methyl-4-(5-iodobenzo[b]furan-3-yl)butanamide

Starting compound: Preparation 65

Preparation 101 N-[2-(5-Iodothieno[3,2-b]pyridin-3-yl)ethyl]acetamide

Starting compound: Preparation 66

Preparation 102 N-[2-(5-Iodo-1H-3-indolyl)ethyl]benzamide

Starting compound: Preparation 67

Preparation 103N-[2-(2-Benzyl-5-iodobenzo[b]furan-3-yl)ethyl]-1-cyclopropane-carboxamide

Starting compound: Preparation 68

Preparation 104 N-[(6-Iodo-2-phenyl-2H-3-chromenyl)methyl]butanamide

Starting compound: Preparation 69

Preparation 105 N-[2-(6-Iodo-2,3-dihydro-1H-1-indenyl)ethyl]acetamide

Starting compound: Preparation 70

Preparation 106 N-[2-(7-Iodo-3-phenyl-1-naphthyl)ethyl]acetamide

Starting compound: Preparation 71

Preparation 107N-[2-(7-Iodo-1,2,3,4-tetrahydro-1-naphthyl)ethyl]acetamide

Starting compound: Preparation 72.1

Preparation 108 N-[2-(5-Iodobenzo[b]furan-3-yl)ethyl]acetamide

Starting compound: Preparation 72

Preparation 109 N-[2-(7-Amino-1-naphthyl)ethyl]-2-phenylacetamide

Step A: N-[2-(7-Vinyl-1-naphthyl)ethyl]-2-phenylacetamide

15 mmol of the product obtained in Preparation 73, 16 mmol ofvinyltributyltin and 0.43 mmol of tetrakis(triphenylphosphine)palladiumare heated in 30 ml of N-methylpyrrolidinone at 110° C. for 3 hours,with stirring. After evaporating off the solvent, the residue is takenup in 20 ml of dichloromethane and treated with 10% aqueous potassiumfluoride solution. After extraction, concentration under reducedpressure and chromatography on silica gel, the pure title product isobtained.

Step B: N-[2-(7-Formyl-1-naphthyl)ethyl]-2-phenylacetamide

To a solution of 10 mmol of the product obtained in Step A in a mixtureof 50 ml of dioxane and 25 ml of water there are added, at ambienttemperature, 1.10 g of osmium tetroxide in 2-methyl-2-propanol and then8.70 g of sodium periodate. After stirring overnight at ambienttemperature, the suspension is filtered and the filtrate is concentratedunder reduced pressure. The residue obtained is taken up indichloromethane. The organic phase is washed with water, dried andevaporated. The residue is purified by chromatography on silica gel toyield the title product.

Step C: 8-{2-[(2-Phenylacetyl)amino]ethyl}-2-naphthoic acid

2.7 g of potassium permanganate in 50 ml of an acetone/water mixture(50/50) are added, at ambient temperature, to a solution of 6.88 mmol ofthe product obtained in Step B in 30 ml of acetone. The solution isstirred for 2 hours at ambient temperature and is then filtered. Thefiltrate is concentrated under reduced pressure and chromatographed onsilica gel to yield the title product.

Step D: 8-{2-[(2-Phenylacetyl)amino]ethyl}-2-naphthalenecarbonylchloride

5 mmol of the product obtained in Step C are dissolved in 40 ml ofthionyl chloride. After stirring under an inert atmosphere for 1 hour,the thionyl chloride is evaporated off under reduced pressure to yieldthe title product.

Step E: N-[2-(7-Amino-1-naphthyl)ethyl]-2-phenylacetamide

A solution of the product obtained in Step D (20 mmol) indichloromethane (30 ml) containing tetrabutylammonium bromide (20 mg) iscooled in an ice bath. After adding sodium azide (24 mmol) dissolved in5 ml of water, the solution is stirred vigorously at 0° C. for 2 hours.The organic phase is separated off, washed with water (2×5 ml) and driedover magnesium sulphate. After filtration, trifluoroacetic acid (30mmol) is added and the solution is stirred under reflux for 60 hours.After cooling, the organic phase is washed with saturated sodiumhydrogen carbonate solution (2×5 ml) and is concentrated under reducedpressure. The residue is then taken up in methanol (20 ml); water (80ml) and then potassium carbonate (30 mmol) are added. After stirring atambient temperature for 20 hours, the reaction mixture is concentratedunder reduced pressure to a volume of about 60 ml and is then extracted3 times with ether (3×50 ml). After drying over sodium sulphate, theorganic phase is filtered and then evaporated under reduced pressure.The residue is chromatographed on silica gel to yield the title product.

In Preparations 110 to 134 the procedure is as in Example 109, startingfrom the appropriate substrate.

Preparation 110 N-[2-(7-Amino-1-naphthyl)ethyl]-2-bromoacetamide

Starting compound: Preparation 94

Preparation 111N-[2-(7-Amino-8-hexyl-1-naphthyl)ethyl]-2-phenylacetamide

Starting compound: Preparation 95

Preparation 112 N-Cyclohexyl-4-(7-amino-1-naphthyl)butanamide

Starting compound: Preparation 96

Preparation 113 N-[3-(7-Amino-1-naphthyl)propyl]acetamide

Starting compound: Preparation 97

Preparation 114 N-[2-(2-Amino-1-naphthyl)-1-methylethyl]propanamide

Starting compound: Preparation 98

Preparation 115 N-[2-(7-Amino-3-benzoyl-1-naphthyl)ethyl]-N′-propylurea

Starting compound: Preparation 78

Preparation 116 N-[2-(7-Amino-1-naphthyl)ethyl]-3-butenamide

Starting compound: Preparation 93

Preparation 117 N-[2-(7-Amino-1-naphthyl)ethyl]acetamide

Starting compound: Preparation 92

Preparation 118N-{2-17-Amino-3-(cyclopropylmethyl)-1-naphthyl]ethyl}acetamide

Starting compound: Preparation 99

Preparation 119 N-Methyl-4-(5-aminobenzo[b]furan-3-yl)butanamide

Starting compound: Preparation 100

Preparation 120 N-[2-(5-Aminothieno[3,2-b]pyridin-3-yl)ethyl]acetamide

Starting compound: Preparation 101

Preparation 121 N-[2-(5-Amino-1H-3-indolyl)ethyl]benzamide

Starting compound: Preparation 102

Preparation 122N-{2-[5-Amino-2-(4-fluorobenzyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]ethyl}acetamide

Starting compound: Preparation 81

Preparation 123N-[2-(5-Amino-2-benzylbenzo[b]furan-3-yl)ethyl]-1-cyclopropane-carboxamide

Starting compound: Preparation 103

Preparation 124 N-[(6-Amino-3,4-dihydro-2H-3-chromenyl)methyl]acetamide

Starting compound: Preparation 82

Preparation 125 N-[(6-Amino-2-phenyl-2H-3-chromenyl)methyl]butanamide

Starting compound: Preparation 104

Preparation 126N-[2-(6-Amino-2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]acetamide

Starting compound: Preparation 87

Preparation 127N-[(9-Amino-2,3-dihydro-1H-benzo[f]chromen-2-yl)methyl]-2-cyclo-propylacetamide

Starting compound: Preparation 88

Preparation 128N-(4-Amino-2,3-dihydro-1H-2-phenalenyl)-N′-cyclopropylthiourea

Starting compound: Preparation 89

Preparation 129 N-[2-(7-Amino-3-phenyl-1-naphthyl)ethyl]acetamide

Starting compound: Preparation 106

Preparation 130N-Cyclobutyl-6-amino-4,5-dihydro-3H-benzo[cd]isobenzofuran-4-carboxamide

Starting compound: Preparation 90

Preparation 131 N-[2-(7-Amino-3-naphthyl-1-naphthyl)ethyl]heptanamide

Starting compound: Preparation 91

Preparation 132 N-[2-(5-Aminobenzo[b]furan-3-yl)ethyl]acetamide

Starting compound: Preparation 108

Preparation 133N-[2-(7-Amino-1,2,3,4-tetrahydro-1-naphthyl)ethyl]acetamide

Starting compound: Preparation 107

Preparation 134 N-[2-(6-Amino-2,3-dihydro-1H-1-indenyl)ethyl]acetamide

Starting compound: Preparation 105

Preparations 135 to 145 are obtained by proceeding as in Preparation 1,starting from the appropriate substrate.

Preparation 135 N-[2-(7-Hydroxy-1-naphthyl)ethyl]-2-furamide Preparation136 N-[2-(7-Hydroxy-1-naphthyl)ethyl]benzamide Preparation 137N-[2-(7-Hydroxy-1-naphthyl)ethyl]cyclopropanecarboxamide Preparation 138N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethyl]benzamide Preparation 139N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethyl]-2-furamide Preparation 140N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethyl]cyclopropanecarboxamidePreparation 141N-[2-(5-Hydroxy-1-benzothiophen-3-yl)ethyl]cyclopropanecarboxamidePreparation 142N-[2-(5-Hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]acetamidePreparation 143N-[2-(5-Hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]cyclopropane-carboxamidePreparation 144N-[2-(5-Hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]benzamidePreparation 145N-[2-(5-Hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-2-furamidePreparation 146N-[2-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]acetamide

The procedure is as in Preparation 40, starting from the compoundobtained in Preparation 142.

Preparation 147N-[2-(5-Iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]acetamide

The procedure is as in Preparation 73, starting from the compoundobtained in Preparation 146.

Preparation 148N-[2-(5-Amino-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]acetamide

The procedure is as in Preparation 109, starting from the compoundobtained in Preparation 147.

Preparation 149N-[2-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-2-furamide

The procedure is as in Preparation 40, starting from the compoundobtained in Preparation 145.

Preparation 150N-[2-(5-Iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-2-furamide

The procedure is as in Preparation 73, starting from the compoundobtained in Preparation 149.

Preparation 151N-[2-(5-Amino-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-2-furamide

The procedure is as in Preparation 109, starting from the compoundobtained in Preparation 150.

Preparation 152N-[2-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]benzamide

The procedure is as in Preparation 40, starting from the compoundobtained in Preparation 144.

Preparation 153N-[2-(5-Iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]benzamide

The procedure is as in Preparation 73, starting from the compoundobtained in Preparation 152.

Preparation 154N-[2-(5-Amino-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]benzamide

The procedure is as in Preparation 109, starting from the compoundobtained in Preparation 153.

Preparation 155N-[2-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide

The procedure is as in Preparation 40, starting from the compoundobtained in Preparation 143.

Preparation 156N-[2-(5-Iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide

The procedure is as in Preparation 73, starting from the compoundobtained in Preparation 155.

Preparation 157N-[2-(5-Amino-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide

The procedure is as in Preparation 109, starting from the compoundobtained in Preparation 156.

Preparation 158N-[2-(5-Hydroxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide

The procedure is as in Preparation 1.

Preparation 159N-[2-(5-Bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide

The procedure is as in Preparation 40, starting from the compoundobtained in Preparation 158.

Preparation 160N-[2-(5-Iodo-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide

The procedure is as in Preparation 73, starting from the compoundobtained in Preparation 159.

Preparation 161N-[2-(5-Amino-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide

The procedure is as in Preparation 109, starting from the compoundobtained in Preparation 160.

Preparation 162N-[2-(5-Hydroxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]acetamide

The procedure is as in Preparation 1.

Preparation 163N-[2-(5-Bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]acetamide

The procedure is as in Preparation 40, starting from the compoundobtained in Preparation 162.

Preparation 164N-[2-(5-Iodo-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]acetamide

The procedure is as in Preparation 73, starting from the compoundobtained in Preparation 163.

Preparation 165N-[2-(5-Amino-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]acetamide

The procedure is as in Preparation 109, starting from the compoundobtained in Preparation 164.

Preparation 166N-[2-(5-Bromo-1-benzofuran-3-yl)ethyl]cyclopropanecarboxamide

The procedure is as in Preparation 40, starting from the compoundobtained in Preparation 140.

Preparation 167N-[2-(5-Iodo-1-benzofuran-3-yl)ethyl]cyclopropanecarboxamide

The procedure is as in Preparation 73, starting from the compoundobtained in Preparation 166.

Preparation 168N-[2-(5-Amino-1-benzofuran-3-yl)ethyl]cyclopropanecarboxamide

The procedure is as in Preparation 109, starting from the compoundobtained in Preparation 167.

Preparation 169 N-[2-(5-Hydroxy-1-benzothiophen-3-yl)ethyl]benzamide

The procedure is as in Preparation 1.

Preparation 170 N-[2-(5-Bromo-1-benzothiophen-3-yl)ethyl]benzamide

The procedure is as in Preparation 40, starting from the compoundobtained in Preparation 169.

Preparation 171 N-[2-(5-Iodo-1-benzothiophen-3-yl)ethyl]benzamide

The procedure is as in Preparation 73, starting from the compoundobtained in Preparation 170.

Preparation 172 N-[2-(5-Amino-1-benzothiophen-3-yl)ethyl]benzamide

The procedure is as in Preparation 109, starting from the compoundobtained in Preparation 171.

Preparation 173 N-[2-(7-Bromo-1-naphthyl)ethyl]-2-furamide

The procedure is as in Preparation 40, starting from the compoundobtained in Preparation 135.

Preparation 174 N-[2-(7-Iodo-1-naphthyl)ethyl]-2-furamide

The procedure is as in Preparation 73, starting from the compoundobtained in Preparation 173.

Preparation 175 N-[2-(5-Bromo-1-benzofuran-3-yl)ethyl]benzamide

The procedure is as in Preparation 40, starting from the compoundobtained in Preparation 138.

Preparation 176 N-[2-(5-Iodo-1-benzofuran-3-yl)ethyl]benzamide

The procedure is as in Preparation 73, starting from the compoundobtained in Preparation 176.

EXAMPLE 1 N-{8-[2-([2-Phenylacetyl]amino)ethyl]-2-naphthyl}butanamide

A solution of butanoic acid chloride (11 mmol) dissolved in ether (5 ml)is added dropwise to a solution of the product obtained in Preparation109 (10 mmol) in ether (10 ml) and triethylamine (2 ml). The solution isstirred at ambient temperature until the amine has disappeared(monitored by TLC). At the end of the reaction, the organic phase iswashed with water, dried, concentrated under reduced pressure andchromatographed on silica gel to yield the title product.

EXAMPLE 2N-{2-[7-{[(Cyclohexylamino)carbonyl]amino}-1-naphthyl]ethyl}-2-phenylacetamide

A solution of cyclohexyl isocyanate in dichloromethane (5 ml) is addedto a solution of the product obtained in Preparation 109 (10 mmol) indichloromethane (10 ml). Stirring is carried out at ambient temperatureuntil the starting amine has disappeared (monitored by TLC); thereaction mixture is then evaporated and concentrated under reducedpressure and is chromatographed on silica gel to yield the titleproduct.

EXAMPLE 3N-{2-[7-([Anilinocarbothioyl]amino)-1-naphthyl]ethyl}-2-phenyl-acetamide

The procedure is as in Example 2, but the cyclohexyl isocyanate isreplaced by phenyl isothiocyanate to obtain the title product.

In Examples 4 to 16 the procedure is as in Example 1, starting fromappropriate reactants.

EXAMPLE 4N-(8-{2-[(2-Bromoacetyl)amino]ethyl}-2-naphthyl)-1-cyclohexane-carboxamide

Starting compound: Preparation 110

EXAMPLE 5N-{1-Hexyl-8-[2-([2-phenylacetyl]amino)ethyl]-2-naphthyl}benzamide

Starting compound: Preparation 111

EXAMPLE 6N-{6-Benzoyl-8-[2-{[(propylamino)carbonyl]amino}ethyl]-2-naphthyl}-2,2-dimethylpropanamide

Starting compound: Preparation 115

EXAMPLE 7N-{3-[4-(Methylamino)-4-oxobutyl]benzo[b]furan-5-yl}-3-butynamide

Starting compound: Preparation 119

EXAMPLE 8N-{3-[2-(Acetylamino)ethyl]-2-[4-fluorobenzyl]-1-methyl-1H-pyrrolo-[2,3-b]pyridin-5-yl}-3-phenyl-2-propenamide

Starting compound: Preparation 122

EXAMPLE 9N-{3-[(Acetylamino)methyl]-3,4-dihydro-2H-6-chromenyl}-2-phenyl-propanamide

Starting compound: Preparation 124

EXAMPLE 10N-{5-[2-(Acetylamino)ethyl]-2,3-dihydro-1,4-benzodioxin-6-yl}-hexanamide

Starting compound: Preparation 126

EXAMPLE 11N-{2-[([2-Cyclopropylacetyl]amino)methyl]-2,3-dihydro-1H-benzo[f]-chromen-9-yl}-4-(trifluoromethyl)benzamide

Starting compound: Preparation 127

EXAMPLE 12N-{2-[([Cyclopropylamino]carbothioyl)amino]-2,3-dihydro-1H-4-phenalenyl}-4-ethoxybenzamide

Starting compound: Preparation 128

EXAMPLE 13N-{8-[2-(Acetylamino)ethyl]-6-phenyl-2-naphthyl}-1-cyclopentane-carboxamide

Starting compound: Preparation 129

EXAMPLE 14N-Cyclobutyl-6-([2-cyclopropylacetyl)amino]-4,5-dihydro-3H-benzo[cd]-isobenzofuran-4-carboxamide

Starting compound: Preparation 130

EXAMPLE 15 N-{8-[2-(Heptanoylamino)ethyl]-2,6-dinaphthyl}-2-butenamide

Starting compound: Preparation 131

EXAMPLE 16N-{2-[6-(Acetylamino)-2,3-dihydro-1H-1-indenyl]ethyl}acetamide

Starting compound: Preparation 134

Examples 17 to 23 are obtained by proceeding as in Example 2, startingfrom appropriate reactants.

EXAMPLE 17N-Cyclohexyl-4-{7-[(anilinocarbonyl)amino]-1-naphthyl}butanamide

Starting compound: Preparation 112

EXAMPLE 18N-{1-Methyl-2-[2-{[([morpholinomethyl]amino)carbonyl]amino}-1-naphthyl]ethyl}propanamide

Starting compound: Preparation 114

EXAMPLE 19N-{2-[7-{[(Benzylamino)carbonyl]amino}-3-(cyclopropylmethyl)-1-naphthyl]ethyl}acetamide

Starting compound: Preparation 118

EXAMPLE 20N-{2-[5-{[(Allylamino)carbonyl]amino}thieno[3,2-b]pyridin-3-yl]ethyl}-acetamide

Starting compound: Preparation 120

EXAMPLE 21N-{2-[2-Benzyl-5-{[(1-ethynylamino)carbonyl]amino}benzo[b]furan-3-yl]ethyl}-1-cyclopropanecarboxamide

Starting compound: Preparation 123

EXAMPLE 22N-{[6-{[([3-Methyl-2-butenyl]amino)carbonyl]amino}-2-phenyl-2H-3-chromenyl]methyl}butanamide

Starting compound: Preparation 125

EXAMPLE 23N-[2-(7-{[(Cyclohexylamino)carbonyl]amino}-3-phenyl-1-naphthyl)-ethyl]acetamide

Starting compound: Preparation 129

In Examples 24 to 29 the procedure is as in Example 3, starting fromappropriate substrates.

EXAMPLE 24N-{2-[7-{[(Isobutylamino)carbothioyl]amino}-1-naphthyl]ethyl}-2-bromoacetamide

Starting compound: Preparation 110

EXAMPLE 25N-{3-[7-{[([4-Methylbenzyl]amino)carbothioyl]amino}-1-naphthyl]-propyl}acetamide

Starting compound: Preparation 113

EXAMPLE 26N-Methyl-4-{5-[([1-ethynylamino]carbothioyl)amino]benzo[b]furan-3-yl}butanamide

Starting compound: Preparation 119

EXAMPLE 27N-{2-[5-{[(Butylamino)carbothioyl]amino}-1H-3-indoly]ethyl}-benzamide

Starting compound: Preparation 121

EXAMPLE 28N-{[9-([Anilinocarbothioyl]amino)-2,3-dihydro-1H-benzo[f]chromen-2-yl]methyl}-2-cyclopropylacetamide

Starting compound: Preparation 127

EXAMPLE 29N-Cyclobutyl-6-{[([2,3-dimethyl-2-butenyl]amino)carbothioyl]amino}-4,5-dihydro-3H-benzo[cd]isobenzofuran-4-carboxamide

Starting compound: Preparation 130

EXAMPLE 30 N-Ethyl-8-{2-[(2-phenylacetyl)amino]ethyl}-2-naphthamide

The procedure is as in Preparation 109, but instead of converting theacid chloride into an amine, it is treated with an amine to yield thetitle amide according to the procedure described below.

A solution of the product obtained in Step D of Preparation 109 (3.5mmol) in ether (10 ml) is added, dropwise, to a solution of ethylamine(4 mmol) in ether (10 ml) and triethylamine (2 ml), maintained between 0and 5° C. using an ice bath. Stirring is carried out at ambienttemperature until the acid chloride has disappeared and the reactionmixture is then poured into a mixture of ice (10 g) and concentrated HCl(0.1 ml). The organic phase is washed with water, dried over magnesiumsulphate, concentrated under reduced pressure and chromatographed onsilica gel to yield the title product.

In Examples 31 to 50 the procedure is as in Example 30, but theethylamine and the product of Step D of Preparation 109 are replaced byappropriate substrates.

EXAMPLE 31N,N-Diethyl-8-{2-[2-1(cyclopropylmethyl)amino]-2-oxoethyl}-2-naphthamide

Starting compound: Preparation 74

EXAMPLE 32N-Phenyl-8-(2-{methyl[(propylamino)carbonyl]amino}ethyl)-2-naphthamide

Starting compound: Preparation 75

EXAMPLE 33N-(1-Ethynyl)-8-{2-[(cyclohexylcarbonyl)amino]ethyl}-2-naphthamide

Starting compound: Preparation 76

EXAMPLE 34N-Benzyl-1-{2-[(2,2,2-trifluoroacetyl)amino]ethyl}-2-naphthamide

Starting compound: Preparation 77

EXAMPLE 35N-{2-[3-Benzoyl-7-(morpholinocarbonyl)-1-naphthyl]ethyl}-N′-propylurea

Starting compound: Preparation 78

EXAMPLE 36N,N-Diphenyl-3-[3-(acetylamino)propyl]benzo[b]furan-5-carboxamide

Starting compound: Preparation 79

EXAMPLE 37N-Isopropyl-N-(2-propynyl)-3-[(acetylamino)methyl]-2-benzylbenzo[b]-thiophene-5-carboxamide

Starting compound: Preparation 80

EXAMPLE 38N,N-Diethyl-3-[2-(acetylamino)ethyl]-2-(4-fluorobenzyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

Starting compound: Preparation 81

EXAMPLE 39 Ethyl2-{[(4-{2-[(2-phenylacetyl)amino]ethyl}-3,4-dihydro-2H-6-chromenyl)carbonyl]amino}acetate

Starting compound: Preparation 83

EXAMPLE 40N-Cyclohexyl-N-(1-ethynyl)-4-[2-(acetylamino)ethyl]-6-thiochroman-carboxamide

Starting compound: Preparation 85

EXAMPLE 41N-Benzyl-3-(2-{[(propylamino)carbonyl]amino}ethyl-1,4-benzodioxin-6-carboxamide

Starting compound: Preparation 86

EXAMPLE 42N-(3-Methyl-2-butenyl)-2-{[(2-cyclopropylacetyl)amino]methyl}-2,3,6,10b-tetrahydro-1H-benzo[f]chromene-8-carboxamide

Starting compound: Preparation 88

EXAMPLE 43N-[3-Phenyl-2-propenyl]-2-{[(cyclopropylamino)carbothioyl]amino}-2,3-dihydro-1H-4-phenalenecarboxamide

Starting compound: Preparation 89

EXAMPLE 44N-Cyclobutyl-N-trityl-4,5-dihydro-3H-benzo[cd]isobenzofuran-4,6-dicarboxamide

Starting compound: Preparation 90

EXAMPLE 45 Ethyl2-[({8-[2-heptanoylamino)ethyl]-6-naphthyl-2-naphthyl}carbonyl)-amino]acetate

Starting compound: Preparation 91

EXAMPLE 46 N-(1-Ethynyl)-8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthamide

Starting compound: Preparation 94

EXAMPLE 47N-Phenyl-1-hexyl-8-{2-[(2-phenylacetyl)amino]ethyl}-2-naphthamide

Starting compound: Preparation 95

EXAMPLE 48 Ethyl2-({[8-[2-(acetylamino)ethyl]-6-(cyclopropylmethyl)-2-naphthyl]-carbonyl}amino)acetate

Starting compound: Preparation 99

EXAMPLE 49N-(1-Ethynyl)-2-benzyl-3-{2-[(cyclopropylcarbonyl)amino]ethyl}benzo-[b]furan-5-carboxamide

Starting compound: Preparation 103

EXAMPLE 50N-(1-Isopropyl-2-propynyl)-3-[(butynylamino)methyl]-2-phenyl-2H-6-chromenecarboxamide

Starting compound: Preparation 104

EXAMPLE 51N-Phenyl-8-(2-{methyl[(propylamino)carbothioyl]amino}ethyl)-2-naphthalenecarbothioamide

The product obtained in Example 32 is treated with Lawesson's reagent toyield the title compound.

In Examples 52 to 57 the procedure is as in Example 51, taking theappropriate starting substrate.

EXAMPLE 52N-Benzyl-1-{2-[(2,2,2-trifluoroethanethioyl)amino]ethyl}-2-naphthalene-carbothioamide

Starting compound: Example 34

EXAMPLE 53N,N-Diphenyl-3-[3-(ethanethioylamino)propyl]benzo[b]furan-5-carbothioamide

Starting compound: Example 36

EXAMPLE 54N,N-Diethyl-3-[2-(ethanethioylamino)ethyl]-2-(4-fluorobenzyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carbothioamide

Starting compound: Example 38

EXAMPLE 55N-Cyclohexyl-N-(1-ethynyl)-4-[2-(ethanethioylamino)ethyl]-6-thiochromancarbothioamide

Starting compound: Example 40

EXAMPLE 56N-(3-Methyl-2-butenyl)-2-{[(2-cyclopropylethanethioyl)amino]methyl}-2,3,6,10b-tetrahydro-1H-benzo[f]chromene-8-carbothioamide

Starting compound: Example 42

EXAMPLE 57N-[3-Phenyl-2-propenyl]-2-{[(cyclopropylamino)carbothioyl]amino}-2,3-dihydro-1H-4-phenalenecarbothioamide

Starting compound. Example 43

In Examples 58 to 61 the procedure is as in Example 1, but the acidchloride is replaced by the corresponding halogenocarboxylate.

EXAMPLE 58 MethylN-{3-[2-(acetylamino)ethyl]benzo[b]furan-5-yl}carbamate

Starting compound: Preparation 132

Melting point=138–140° C.

EXAMPLE 59 EthylN-(8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthyl)carbamate

Starting compound: Preparation 110

EXAMPLE 60 MethylN-{8-[2-(acetylamino)ethyl]-6-phenyl-2-naphthyl}carbamate

Starting compound: Preparation 129

EXAMPLE 61 HexylN-{8-[2-(acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}-carbamate

Starting compound: Preparation 133

EXAMPLE 62 N-[2-(5-Methoxycarbonylbenzo[b]furan-3-yl)ethyl]acetamide

Step A: 3-Acetyl-4-hydroxybenzoic acid

166 mmol of aluminium chloride are added slowly to 150 ml ofnitrobenzene. 83 mmol of 4-acetylbenzoic acid are then added and heatingis carried out at 120° C. for 2 hours. The mixture is hydrolysed using1.2 litres of ice-cold water and the aqueous phase is acidified with 20ml of concentrated HCl. Then, extraction with ethyl acetate and washingwith aqueous 5% sodium carbonate solution are carried out. The aqueousphase is acidified with 6N HCl and the precipitate obtained is dried andrecrystallised.

Melting point=120–121° C.

Step B: 3-(2-Bromoacetyl)-4-hydroxybenzoic acid

The compound obtained in Step A (32.2 mmol) is dissolved in glacialacetic acid (40 ml) and then 48.3 mmol of bromine are added. The mixtureis heated at 80° C. for 2 hours and is then hydrolysed using ice-coldwater. The precipitate obtained is filtered off, washed with water untila pH of 5–6 is obtained, and then dried and recrystallised.

Melting point=174–1 75° C.

Step C: Methyl 3-bromoacetyl-4-hydroxybenzoate

The compound obtained in Step B (27.4 mmol) is dissolved in 150 ml ofMeOH, and 54.8 mmol of thionyl chloride are added dropwise in the coldstate. The mixture is then stirred for 1 hour at ambient temperature andthen for 2 hours at reflux. After evaporating off the methanol and thethionyl chloride, the oily residue is taken up in AcOEt, washed withwater and then dried over MgSO₄. The solvent is evaporated off underreduced pressure and the solid obtained is recrystallised.

Melting point=93–94° C.

Step D: 5-(Methoxycarbonyl-3-benzo[b]furan-3-yl)acetonitrile

The compound obtained in Step C (15 mmol) is dissolved in 35 ml ofacetone. 30 mmol of potassium carbonate are added and the mixture isstirred for 2 hours at ambient temperature. The precipitate formed isfiltered off, washed with acetone and the filtrate is evaporated underreduced pressure. The benzofiranone formed is used directly in thefollowing step:

-   -   22.5 mmol of NaH are introduced into a 250 ml round-bottomed        two-necked flask which is placed in a bath of ice/salt and under        a nitrogen atmosphere. 22.5 mmol of diethyl cyanophosphonate are        added dropwise and the mixture is then stirred for 20 minutes.        The benzofuranone previously obtained, in 140 ml of anhydrous        THF, is added and the mixture is stirred for 2 hours at ambient        temperature. After hydrolysing on a pile of ice and extracting        with Et₂O, the organic phase is dried over MgSO₄ and the solvent        is then evaporated off under reduced pressure. The title        compound is purified by chromatography on a silica gel column        (eluant: CH₂Cl₂), and is then recrystallised.

Melting point=125–126° C.

Step E: N-[2-(5-Methoxycarbonylbenzo[b]furan-3-yl)ethyl]acetamide

The 5-(methoxycarbonylbenzo[b]furan-3-yl)acetonitrile obtained in Step D(6.46 mmol) is dissolved in acetic anhydride (30 ml) in an autoclave,and 14.4 mmol of Raney nickel are added. After stirring overnight at 60°C. and under a hydrogen pressure of 60 bars, the catalyst is filteredoff and washed with methanol. The filtrate is evaporated to dryness andthe chestnut-coloured precipitate obtained is chromatographed on asilica gel column using ethyl acetate as eluant and is thenrecrystallised.

Melting point=121–122° C.

Elemental Microanalysis:

C H N % calculated: 64.36 5.78 5.36 % found: 64.14 5.81 5.28

EXAMPLE 63 Methyl 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxylate

Step A: Methyl 3-(2-aminoethyl)-1-benzofuran-5-carboxylate hydrochloride

6.57 mmol of the compound obtained in Step D of Example 62 are dissolvedin 150 ml of methanol. The solution is introduced into an autoclave and28.8 mmol of Raney nickel are added. The solution is saturated withammonia, and then hydrogen is introduced until a pressure of 60 bars isobtained. The solution is stirred for 4 hours at a temperature of 60° C.After cooling, the catalyst is filtered off, and the methanol is thenevaporated off. The residue is purified by chromatography on a silicagel column using a mixture of dichloromethane/methanol (7/3) and thenmethanol as eluant. The amine obtained is dissolved in absolute ethanol.Stirring is carried out in an ice bath and gaseous hydrogen chloride isbubbled through. The hydrochloride obtained is filtered off undersuction and dried in a desiccator.

Melting point=210–211° C.

Step B: Methyl 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxylate

1 mmol of the compound obtained in Step A is introduced into 30 ml ofanhydrous CH₂Cl₂. The temperature is lowered with the aid of an icebath, and 1.5 mmol of triethylamine and then 1.5 mmol of 2-furoic acidchloride are added dropwise in succession. The mixture is stirred for 20minutes, and the organic phase is then washed with water, dried overMgSO₄ and evaporated. The residue is purified by chromatography on asilica gel column and the title product is recrystallised.

Melting point=116–118° C.

Elemental Microanalysis:

C H N % calculated: 65.17 4.82 4.47 % found: 64.80 4.84 4.50

EXAMPLE 64 Methyl3-{2-[(cyclopentylcarbonyl)amino]ethyl}1-benzofuran-5-carboxylate

The procedure is as in Example 63.

Melting point=122–123° C.

EXAMPLE 65 Methyl3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxylate

The procedure is as in Example 63.

Melting point=154–155° C.

EXAMPLE 66 Methyl3-[2-(3-butenoylamino)ethyl]-1-benzofuran-5-carboxylate

Vinylacetic acid (1 mmol),1-ethyl-3-(3-dimethylaminopropyl-3-ethyl)carbodiimide hydro-chloride(E.D.C.) (1.1 mmol) and hydroxybenzotriazole (HOBT) (1.1 mmol) aredissolved in dichloromethane (30 ml) in a flask cooled to −20° C. After30 minutes, the compound obtained in Step A of Example 63 (1 mmol),dissolved in dichloromethane (20 ml), is added dropwise. The reactionmixture is stirred for 30 minutes at −20° C. and then overnight atambient temperature. The dichloromethane is evaporated off and theresidue is purified by chromatography on a silica gel column.

Melting point=98–100° C.

EXAMPLE 67 3-[2-(Acetylamino)ethyl]-1-benzofuran-5-carboxamide

The ester (0.1 mol) obtained in Example 62, dissolved in an aqueous 20%ammonium hydroxide solution (50 ml), is heated for 5 hours at 60° C. Thereaction mixture is cooled and is then evaporated to dryness. Theresidue obtained is purified by chromatography on a silica gel column.

Melting point=206–208° C.

Elemental Microanalysis:

C H N % calculated: 63.40 5.73 11.38 % found: 63.23 5.89 11.17

EXAMPLE 683-{2-[(Cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxamide

The same procedure is used as in Example 67.

Melting point=209–210° C.

EXAMPLE 69 3-[2-(2-Furoylamino)ethyl]-1-benzofuran-5-carboxamide

The same procedure is used as in Example 67.

Melting point=110–112° C.

Elemental Microanalysis:

C H N % calculated: 64.42 4.73 9.39 % found: 64.23 4.98 9.97

EXAMPLE 703-{2-[(Cyclopropylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxamide

To the ester obtained in Example 62 (1 mmol), dissolved in methanol (40ml) in the hot state, there is added an aqueous 40% methylamine solution(1.6 mmol), and the mixture is refluxed for 2 hours. The reactionmixture is then cooled and the methanol is subsequently evaporated off.The aqueous phase is extracted with ethyl acetate, the organic phase isdried over magnesium sulphate and the solvent is evaporated off. Theresidue is purified by chromatography on a silica gel column.

Melting point=188–189° C.

Elemental Microanalysis:

C H N % calculated: 67.11 6.34 9.78 % found: 67.00 6.34 9.77

EXAMPLE 71 3-[2-(Acetylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide

The same procedure is used as in Example 70.

Melting point=158–159° C.

Elemental Microanalysis:

C H N % calculated: 64.59 6.20 10.76 % found: 64.27 6.13 10.44

EXAMPLE 723-{2-[(Cyclopentylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxamide

The same procedure is used as in Example 70.

Melting point=170–171° C.

EXAMPLE 73 3-[2-(Benzoylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide

The same procedure is used as in Example 70.

EXAMPLE 74N-{3-[2-(Acetylamino)ethyl]-1-benzofuran-5-yl}-2,2,2-trifluoroacetamide

Step A: 3-[2-(Acetylamino)ethyl]-1-benzofuran-5-carboxylic acid

To the ester obtained in Example 62 (2 mmol), dissolved in methanol (90ml), there is added aqueous 30% sodium hydroxide solution (30 ml), andthe mixture is stirred overnight. After evaporating off the methanol,the temperature of the reaction mixture is lowered with the aid of anice bath and the mixture is acidified with hydrochloric acid solution(6N). The aqueous phase is extracted with ethyl acetate, and the organicphase is dried over magnesium sulphate and then evaporated to dryness.The residue obtained is recrystallised.

Melting point=210–211° C.

Step B: 3-[2-(Acetylamino)ethyl]-1-benzofuran-5-carbonyl azide

The acid (1 mmol) obtained in Step A is dissolved in acetone. Thetemperature of the reaction mixture is lowered with the aid of an icebath, and triethylamine (1.5 mmol) and then ethyl chloroformate (1.5mmol) are added. After stirring for 15 minutes, sodium azide (1.5 mmol),previously dissolved in water (1 ml of water per 400 mg of sodiumazide), is added and stirring is again carried out for 10 minutes. Themixture is extracted with ethyl acetate, and the organic phase is thenwashed with water, dried over magnesium sulphate and evaporated todryness. The azide obtained is used, without additional purification, inthe following Step.

Step C:N-{3-[2-(Acetylamino)ethyl]-1-benzofuran-5-yl}-2,2,2-trifluoroacetamide

To the azide obtained in Step B (460 mg, 1.68 mmol), dissolved indichloromethane, there is added trifluoroacetic acid (1.82 ml, 2.35mmol) and stirring is carried out overnight. The reaction mixture iswashed with water and then with aqueous 10% sodium hydrogen carbonatesolution.

The organic phase is dried over magnesium sulphate and then evaporated.The residue obtained is purified by chromatography on a silica gelcolumn using ethyl acetate as eluant.

Melting point=152–154° C.

EXAMPLE 75 Methyl3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-yl-carbamate

The azide obtained in Step B of Example 74 (1 mmol) is heated at 80° C.overnight and 5 ml of MeOH and 5 ml of toluene are added. Afterevaporating off the solvent, the residue obtained is purified bychromatography on a silica gel column.

Melting point=153–155° C.

Elemental Microanalysis:

C H N % calculated: 63.56 6.00 9.27 % found: 63.27 6.02 9.14

EXAMPLE 76 tert-Butyl3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-carbamate

The procedure is as in Examples 74 and 75.

Melting point=146–148° C.

Elemental Microanalysis:

C H N % calculated: 64.12 6.97 8.79 % found: 64.03 6.58 8.67

EXAMPLE 77 tert-Butyl3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-(methyl)carbamate

To 1.98 mmol of the carbamate obtained in Example 76, dissolved indimethylformamide, there are added, in the cold state, 2.18 mmol ofsodium hydride, and stirring is carried out for 2 hours at ambienttemperature. 2.37 mmol of methyl iodide are added to the mixture andstirring is carried out for 4 hours at ambient temperature. The reactionmixture is hydrolysed, extracted with ethyl acetate, and the organicphase is then washed with water and dried over magnesium sulphate. Theresidue is recrystallised.

EXAMPLE 78 Methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-yl-carbamate

The procedure is as in Examples 74 and 75.

EXAMPLE 79 Methyl3-[2-(isobutyrylamino)ethyl]-1-benzofuran-5-yl-carbamate

The procedure is as in Examples 74 and 75.

EXAMPLE 80 N-{2-[7-(Aminosulphonyl)-1-naphthyl]ethyl}acetamide

Step A: N-{2-[7-(Benzylthio)-1-naphthyl]ethyl}acetamide

4.4 mmol of the compound obtained in Preparation 1 are dissolved in 20ml of anhydrous CH₂Cl₂ and placed under a current of nitrogen. 6.5 mmolof benzylthiol are added dropwise using a syringe and then 8.8 mmol oftriflic acid are added, before the mixture is refluxed for 24 hours.After cooling, hydrolysis is carried out using 10% Na₂CO₃ solution. Theorganic phase is washed with 10% sodium hydroxide solution and then withwater until the washing waters are neutral, and is then dried andevaporated. The residue is taken up in petroleum ether andrecrystallised from a toluene/cyclohexane mixture.

Melting point=80–83° C.

Step B: 8-[2-(Acetylamino)ethyl]-2-naphthalenesulphonyl chloride

3 mmol of the compound obtained in Step A are crushed in a mortar,together with 13.1 mmol of iodosobenzene and 107 g of silica/HCl, withthe aid of a pestle. Dichloromethane is added and the silica is filteredoff and washed several times with CH₂Cl₂. The filtrate obtained isevaporated and the residue is taken up in petroleum ether and thenfiltered.

Step C: N-{2-[7-(Aminosulphonyl)-1-naphthyl]ethyl}acetamide

0.8 mmol of the compound obtained in Step B is dissolved in 10 ml ofCH₂Cl₂ and then 1.2 mmol of triethylamine are added. The mixture iscooled with the aid of an ice bath and 1.2 mmol of ammonium hydroxidesolution are added dropwise. After stirring for 2 hours, the mixture isevaporated and the residue obtained is recrystallised.

Melting point=194–196° C.

EXAMPLE 81 N-(2-{7-[(Methylamino)sulphonyl]-1-naphthyl}ethyl)acetamide

The procedure is as in Example 80, but the ammonium hydroxide in Step Cis replaced by methylamine.

Melting point=155–156° C.

By proceeding as in Example 80, but replacing, in Step A, the compoundof Preparation 1 by the appropriate substrate, and, in Step C, theammonium hydroxide by the appropriate amine, Examples 82 to 84 areobtained:

EXAMPLE 82 N-(2-{7-[(Methylamino)sulphonyl]-1-naphthy}ethyl)-2-furamide

Starting compound: Preparation 135

EXAMPLE 83 N-(2-{7-[(Ethylamino)sulphonyl]-1-naphthyl}ethyl)benzamide

Starting compound: Preparation 136

EXAMPLE 84N-(2-{7-[(Methylamino)sulphonyl]-1-naphthyl}ethyl)cyclopropane-carboxamide

Starting compound: Preparation 137

EXAMPLE 85N-(3-{5-[(Methylamino)sulphonyl]-1-benzofuran-3-yl}propyl)acetamide

Starting compound: Preparation 16

EXAMPLE 86N-(2-{5-[(Propylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)acetamide

Starting compound: Preparation 18

EXAMPLE 87N-(2-{5-[(Cyclopropylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)-benzamide

Starting compound: Preparation 138

EXAMPLE 88N-(2-{5-[(Methylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)-2-furamide

Starting compound: Preparation 139

EXAMPLE 89N-(2-{5-[(Hexylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)cyclopropane-carboxamide

Starting compound: Preparation 140

EXAMPLE 90N-(2-{5-[(Methylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)cyclopropane-carboxamide

Starting compound: Preparation 140

EXAMPLE 91N-(2-{2-Benzyl-5-[(methylamino)sulphonyl]-1-benzothiophen-3-yl}ethyl)-acetamide

Starting compound: Preparation 19

EXAMPLE 92N-(2-{5-[(Isopropylamino)sulphonyl]-1-benzothiophen-3-yl}ethyl)-cyclopropanecarboxamide

Starting compound: Preparation 141

EXAMPLE 93N-(2-{5-[(Methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)-acetamide

Starting compound: Preparation 142

EXAMPLE 94N-(2-{5-[(Methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)-cyclopropanecarboxamide

Starting compound: Preparation 143

EXAMPLE 95N-(2-{5-[(Methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)-benzamide

Starting compound: Preparation 144

EXAMPLE 96N-(2-{5-[(Methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)-2-furamide

Starting compound: Preparation 145

Examples 97 to 105 are obtained by proceeding as in Example 1, butreplacing the acid chloride by the corresponding halogenocarboxylate.

EXAMPLE 97 Methyl5-[(acetylamino)methyl]-2,3-dihydro-1,4-benzodioxin-6-yl-carbamate

Starting compound: Preparation 126

EXAMPLE 98 Methyl3-[(acetylamino)methyl]-3,4-dihydro-2H-chromen-6-yl-carbamate

Starting compound: Preparation 124

EXAMPLE 99 Ethyl3-[2-(acetylamino)ethyl]-2,3-dihydro-1H-inden-5-yl-carbamate

Starting compound: Preparation 134

EXAMPLE 100 Methyl3-[2-(acetylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate

Starting compound: Preparation 148

EXAMPLE 101 Methyl3-[2-(2-furoylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate

Starting compound: Preparation 151

EXAMPLE 102 Methyl3-[2-(benzoylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate

Starting compound: Preparation 154

EXAMPLE 103 Methyl3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1H-pyrrolo[2,3-b]-pyridin-5-yl-carbamate

Starting compound: Preparation 157

EXAMPLE 104 Methyl3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1H-pyrrolo[3,2-b]-pyridin-5-yl-carbamate

Starting compound: Preparation 161

EXAMPLE 105 Ethyl3-[2-(acetylamino)ethyl]-1H-pyrrolo[3,2-b]pyridin-5-yl-carbamate

Starting compound: Preparation 165

Examples 106 to 108 are obtained by proceeding as in Example 1, startingfrom the appropriate substrate.

EXAMPLE 106 N-{8-[2-(Acetylamino)ethyl]-2-naphthyl}acetamide

Starting compound: Preparation 117

EXAMPLE 107N-{2-[5-(Acetylamino)-1-benzofuran-3-yl]ethyl}cyclopropane-carboxamide

Starting compound: Preparation 168

EXAMPLE 108 N-{2-[5-(Acetylamino)-1-benzothiophen-3-yl]ethyl}benzamide

Starting compound: Preparation 172

Examples 109 to 112 are obtained by proceeding as in Preparation 109,condensing the appropriate amine with the intermediate acid chloride.

EXAMPLE 1093-[2-(Acetylamino)ethyl]-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

Starting compound: Preparation 147

EXAMPLE 110 N-(2-{7-[(Methylamino)carbonyl]-1-naphthyl}ethyl)-2-furamide

Starting compound: Preparation 174

EXAMPLE 1113-{2-[(Cyclopropylcarbonyl)amino]ethyl}-N-ethyl-1-benzofuran-5-carboxamide

Starting compound: Preparation 167

EXAMPLE 112 3-[2-(Benzoylamino)ethyl]-N-ethyl-1-benzofuran-5-carboxamide

Starting compound: Preparation 176

EXAMPLE 113N-{8-[2-(Acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}acetamide

Step A: 7-Nitro-3,4-dihydro-1(2H)-naphthalenone

7 mmol of 1-oxo-1,2,3,4-tetrahydronaphthalene and 5 ml of concentratedsulphuric acid are cooled in a freezer for 30 minutes. The reactionmixture is then placed in a bath of alcohol at −15° C. on a coolingplate. A sulphonitric mixture (1.1 ml of sulphuric acid and 0.73 ml ofnitric acid) is prepared and brought to the temperature of the reactionmixture before being added dropwise, avoiding any drastic heating of themixture. Stirring is carried out for 15 minutes and then hydrolysis on apile of ice is carried out. The pale yellow precipitate obtained iswashed with water until the washing waters have a neutral pH and is thendried in a desiccator and purified on a silica gel column.

Melting point=103.7–104.3° C.

Step B: 2-[7-Nitro-3,4-dihydro-1(2H)-naphthalenylidene]acetonitrile

Using a 50 ml two-necked flask under a current of nitrogen and placed ina bath of alcohol at −15° C., 0.32 g of sodium hydride is added inportions to 40 ml of THF, with magnetic stirring, and then 1.4 g ofdiethyl cyanomethylphosphonate in 10 ml of THF are added dropwise. Afterstirring for half an hour, when the mixture is highly homogeneous, theflask is plunged into a medium at −78° C. (cryostat), and 1 g of thecompound obtained in Step A, dissolved in 20 ml of THF, is addeddropwise. Stirring under a current of nitrogen is carried out for 2hours. The reaction mixture is then brought to ambient temperature,hydrolysed on ice and precipitated. After filtering under suction andwashing with water until the washing waters have a neutral pH,extraction with 3 volumes of ether is carried out. The organic phasesare washed with 3 volumes of water and then dried. The grey solidobtained is decolorised on carbon.

Melting point=98.1–98.5° C.

Step C:N-{8-[2-(Acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}acetamide

9 mmol of the compound obtained in Step B are dissolved in aceticanhydride (100 ml) and then a small spatula of sodium acetate is added.The mixture is introduced into an autoclave, Raney nickel is added andautoclaving under a pressure of 40 bars is carried out for 6 hours, withstirring at 50–60° C. The mixture is filtered and is rinsed with alcoholat 95° C.; the solvent is then evaporated off. Hydrolysis is carried outusing 100 ml of distilled water and extraction with 3 volumes ofdichloromethane is carried out. The organic phase is washed with 2volumes of water, dried over magnesium sulphate, filtered andevaporated. Rinsing with an ether/dichloromethane mixture andtrituration in ether are carried out. The light-beige solid obtained isrecrystallised.

Melting point=127.7–128.7° C.

Elemental Microanalysis:

C H N % calculated: 70.04 8.08 10.21 % found: 69.74 8.14 10.43

EXAMPLE 114 Methyl 8-[2-(acetylamino)ethyl]-2-naphthyl-carbamate

The procedure is as in Example 97.

Starting compound: Preparation 117

EXAMPLE 115N-[2-(1,3-Dioxo-1,2,3,4-tetrahydrobenzo[f]quinolin-10-yl)ethyl]-2-phenyl-acetamide

A solution of the product obtained in Preparation 109 (10 mmol) in ether(160 ml) is added very slowly, using a dropper to a solution of malonyldichloride (40 mmol) in ether (40 ml) and triethylamine (2 ml). At theend of the reaction, the reaction mixture is concentrated under reducedpressure. The residue is dried using a vane pump and then taken up inether. The organic phase is washed with water, dried over magnesiumsulphate, concentrated under reduced pressure and then dried using avane pump. The residue is then taken up in 100 ml of1,1,2,2-tetrachloroethane. The resulting solution is then added dropwiseto a solution of aluminium chloride (30 mmol) in 50 ml of the samesolvent under nitrogen. The mixture is heated at 60° C. until thereaction has ceased; the reaction mixture is then poured into a mixtureof ice (20 g) and concentrated HCl (1 ml) and is stirred for one hour.The aqueous phase is extracted twice with chloroform and then thecombined organic phases are dried over magnesium sulphate andconcentrated under reduced pressure. The residue is chromatographed onsilica gel to yield the title product.

In Examples 116 to 120 the procedure is as in Example 115, starting fromappropriate substrates.

EXAMPLE 116N-Cyclohexyl-4-(1,3-dioxo-1,2,3,4-tetrahydrobenzo[f]quinolin-10-yl)-butanamide

Starting compound: Preparation 112

EXAMPLE 117N-[2-(7-Benzoyl-1,2-dioxo-2,3-dihydro-1H-benzo[e]indol-9-yl)ethyl]-N′-propylurea

Starting compound: Preparation 115

EXAMPLE 118N-Methyl-4-(7,9-dioxo-6,7,8,9-tetrahydrofuro[3,2-f]quinolin-1-yl)-butanamide

Starting compound: Preparation 119

EXAMPLE 119N-{2-[2-(4-Fluorobenzyl)-3-methyl-7,8-dioxo-3,6,7,8-tetrahydro-dipyrrolo[2,3-b:3,2-d]pyridin-1-yl]ethyl}acetamide

Starting compound: Preparation 122

EXAMPLE 120N-[(8,10-Dioxo-2,3,7,8,9,10-hexahydro-1H-pyrano[3,2-f]quinolin-2-yl)-methyl]acetamide

Starting compound: Preparation 124

EXAMPLE 121N-[2-(3-Oxo-1,2,3,4-tetrahydrobenzo[f]quinolin-10-yl)ethyl]-2-phenyl-acetamide

The product of Example 115 (3 mmol) is dissolved in acetic acid (70 ml).After several purges with argon, 10% palladium-on-carbon (600 mg) isadded and the mixture is placed under a hydrogen atmosphere. Stirring iscarried out at ambient temperature until the end of the reaction(monitored by TLC) and the palladium is filtered off over Celite. Theacetic acid is evaporated off to dryness and the residue ischromatographed on silica gel to yield the title product.

In Examples 122 to 126 the procedure is as in Example 121, starting fromappropriate substrates.

EXAMPLE 122N-Cyclohexyl-4-(3-oxo-1,2,3,4-tetrahydrobenzo[f]quinolin-10-yl)-butanamide

Starting compound: Example 116

EXAMPLE 123N-[2-(7-Benzoyl-2-oxo-2,3-dihydro-1H-benzo[e]indol-9-yl)ethyl]-N′-propylurea

Starting compound: Example 117

EXAMPLE 124N-Methyl-4-(9-oxo-6,7,8,9-tetrahydrofuro[3,2-f]quinolin-1-yl)-butanamide

Starting compound: Example 118

EXAMPLE 125N-{2-[2-(4-Fluorobenzyl)-3-methyl-8-oxo-3,6,7,8-tetrahydropyrrolo-[2,3-b:3,2-d]pyridin-1-yl]ethyl}acetamide

Starting compound: Example 119

EXAMPLE 126N-[(8-Oxo-2,3,7,8,9,10-hexahydro-1H-pyrano[3,2-f]quinolin-2-yl)-methyl]acetamide

Starting compound: Example 120

EXAMPLE 127

N-[2-(4-Oxo-3,4-dihydrobenzo[f]isoquinolin-10-yl)ethyl]-1-cyclohexane-carboxamide

The product of Example 33 (10 mmol) and triethylene glycol areintroduced into a two-necked flask. Heating is carried out at 160–170°C., under nitrogen and with stirring, for five hours. The reactionmixture is poured into ice-cold water and is extracted with ethylacetate. The organic phase is washed with water and dried over calciumchloride. After filtration, the organic phase is concentrated underreduced pressure. The residue is chromatographed on silica gel to yieldthe title product.

In Examples 128 to 132, the procedure is as in Example 127, startingfrom appropriate substrates.

EXAMPLE 128N-[2-(2-Benzyl-7-isopropyl-6-oxo-6,7-dihydrothieno[3,2-f]isoquinolin-1-yl)ethyl]acetamide

Starting compound: Example 37

EXAMPLE 129N-[2-(3-Cyclohexyl-4-oxo-3,8,9,10-tetrahydro-4H-thiopyrano[3,2-f]-isoquinolin-10-yl)ethyl]acetamide

Starting compound: Example 40

EXAMPLE 130N-[2-(4-Oxo-3,4-dihydrobenzo[f]isoquinolin-10-yl)ethyl]-2-bromo-acetamide

Starting compound: Example 46

EXAMPLE 131N-[2-(2-Benzyl-6-oxo-6,7-dihydrofuro[3,2-f]isoquinolin-1-yl)ethyl]-1-cyclopropanecarboxamide

Starting compound: Example 49

EXAMPLE 132N-[(9-Isopropyl-7-oxo-3-phenyl-3,7,8,9-tetrahydrochromeno[6,5-c]-azepin-2-yl)methyl]butanamide

Starting compound: Example 50

EXAMPLE 133N-[2-(1,4-Dioxo-1,3,4,8,9,10-hexahydro-2H-pyrano[3,2-f]isoquinolin-10-yl)ethyl]-2-phenylacetamide

Step A:2-{[(4-{2-[(2-Phenylacetyl)amino]ethyl}-3,4-dihydro-2H-chromen-6-yl-carbonyl]amino}aceticacid

A 0.5N aqueous solution of K₂CO₃ (10 ml) is added to the productobtained in Example 39 (4 mmol) dissolved in methanol (10 ml). When thereaction has ceased, the solution is acidified to pH 6–7 using 1Nhydrochloric acid solution. The reaction mixture is extracted withdichloromethane. The organic phase is washed with water, dried overmagnesium sulphate and Is concentrated under reduced pressure. Theresidue is chromatographed on silica gel to yield the title product.

Step B:2-{[(4-{2-[(2-Phenylacetyl)amino]ethyl}-3,4-dihydro-2H-chromen-6-yl-carbonyl]amino}acetylchloride

The product obtained in Step A (3 mmol), dissolved in thionyl chloride,is stirred at 60° C. under a current of nitrogen for one hour. Thethionyl chloride is evaporated off under reduced pressure and theresidue is dried with the aid of a vane pump to yield the title product.

Step C:N-[2-(1,4-Dioxo-1,3,4,8,9,10-hexahydro-2H-pyrano[3,2-f]isoquinolin-10-yl)-ethyl]-2-phenylacetamide

The product obtained in Step B (3 mmol), dissolved in1,1,2,2-tetrachloroethane (30 ml), is added dropwise to a solution ofaluminium chloride (10 mmol) in the same solvent (20 ml) under nitrogen.The reaction mixture is heated at 60° C., with stirring, until thereaction has ceased. The solution is then poured into a mixture of ice(10 g)/concentrated HCl (0.3 ml) and stirring is carried out for onehour. The aqueous phase is extracted twice with chloroform; the combinedorganic phases are then dried over magnesium sulphate and concentratedunder reduced pressure. The residue is chromatographed on silica gel toyield the title product.

In Examples 134 to 135 the procedure is as in Example 133, starting fromappropriate reactants.

EXAMPLE 134N-[2-(1,4-Dioxo-8-naphthyl-1,2,3,4-tetrahydro[f]isoquinolin-10-yl)-ethyl]heptanamide

Starting compound: Example 45

EXAMPLE 135N-{2-[8-(Cyclopropylmethyl)-1,4-dioxo-1,2,3,4-tetrahydrobenzo[f]-isoquinolin-10-yl]ethyl}acetamide

Starting compound: Example 48

In Examples 136 to 138 the procedure is as in Example 122, starting fromappropriate substrates.

EXAMPLE 136N-[2-(4-Oxo-1,3,4,8,9,10-hexahydro-2H-pyrano[3,2-f]isoquinolin-10-yl)-ethyl]-2-phenylacetamide

Starting compound: Example 133

EXAMPLE 137N-[2-(4-Oxo-8-naphthyl-1,2,3,4-tetrahydrobenzo[f]isoquinolin-10-yl)-ethyl]heptanamide

Starting compound: Example 134

EXAMPLE 138N-{2-[8-(Cyclopropylmethyl)-4-oxo-1,2,3,4-tetrahydrobenzo[f]-isoquinolin-10-yl]ethyl}acetamide

Starting compound: Example 135

EXAMPLE 139N-[2-(4-Thioxo-3,4-dihydrobenzo[f]isoquinolin-10-yl)ethyl]-1-cyclohexanecarbothioamide

The product obtained in Example 127 is treated with Lawesson's reagentto yield the title compound. Examples 140 to 142 are obtained byproceeding as in Example 139.

EXAMPLE 140N-[2-(3-Cyclohexyl-4-thioxo-3,8,9,10-tetrahydro-4H-thiopyrano[3,2-f]-isoquinolin-10-yl)ethyl]acetamide

Starting compound: Example 129

EXAMPLE 141N-[2-(1,4-Dithioxo-1,3,4,8,9,10-hexahydro-2H-pyrano[3,2-f]isoquinolin-10-yl)ethyl]-2-phenylethanethioamide

Starting compound: Example 133

EXAMPLE 142N-{2-[8-(Cyclopropylmethyl)-4-thioxo-1,2,3,4-tetrahydrobenzo[f]-isoquinolin-10-yl]ethyl}ethanethioamide

Starting compound: Example 138

EXAMPLE 143N-Cyclohexyl-4-(1-hydroxy-3-oxo-1,2,3,4-tetrahydrobenzo[f]quinolin-10-yl)butanamide

A solution of the product obtained in Example 116 (2 mmol) dissolved inmethanol (10 ml) is added dropwise to a suspension of sodium hydride(2.2 mmol) in methanol (50 ml) at −40° C. Stirring is carried out untilthe starting compound has completely disappeared (about 3 hours). At theend of the reaction, the solution is poured into water (30 ml). Thereaction mixture is concentrated under reduced pressure to a volume ofabout 30 ml and is then extracted with ethyl acetate. The aqueous phaseis washed with water, dried over magnesium sulphate and concentratedunder reduced pressure. The residue is chromatographed on silica gel toyield the title product.

In Examples 144 and 145, the procedure is as in Example 143.

EXAMPLE 144N-[(10-Hydroxy-8-oxo-2,3,7,8,9,10-hexahydro-1H-pyrano[3,2-f]quinolin-2-yl)methyl]acetamide

Starting compound: Example 120

EXAMPLE 145N-[2-(1-Hydroxy-4-methyl-1,2,3,4-tetrahydrobenzo[f]quinolin-10-yl)ethyl]-2-phenylacetamide

Starting compound: Example 133

EXAMPLE 146 Methyl3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-yl-carbamate

The procedure is as in Examples 74 and 75.

EXAMPLE 147 Methyl3-{2-[(cyclopentylcarbonyl)amino]ethyl}-1-benzofuran-5-yl-carbamate

The procedure is as in Examples 74 and 75.

EXAMPLE 148 Methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxylate

The procedure is as in Example 63.

EXAMPLE 149 Methyl 3-[2-(isobutylamino)ethyl]-1-benzofuran-5-carboxylate

The procedure is as in Example 63.

EXAMPLE 150 3-[2-(Benzoylamino)ethyl]-1-benzofuran-5-carboxamide

The procedure is as in Example 67.

EXAMPLE 151 Methyl 8-[2-(3-butenoylamino)ethyl]-2-naphthyl-carbamate

The procedure is as in Examples 74 and 75.

EXAMPLE 152 N-{8-[2-(Acetylamino)ethyl]-2-naphthyl}-4-fluorobenzamide

The procedure is as in Example 1, starting from the compound obtained inPreparation 117.

EXAMPLE 153 Ethyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxylate

The procedure is as in Example 62.

Pharmacological Study EXAMPLE A Acute Toxicity Study

Acute toxicity was evaluated after oral administration to groups eachcomprising 8 mice (26±2 grams). The animals were observed at regularintervals during the course of the first day, and daily for the twoweeks following treatment. The LD₅₀ (dose that causes the death of 50%of the animals) was evaluated and demonstrated the low toxicity of thecompounds of the invention.

EXAMPLE B: Melatonin Receptor Binding Study on Pars Tuberalis Cells ofSheep

Melatonin receptor binding studies of the compounds of the inventionwere carried out according to conventional techniques on pars tuberaliscells of sheep. The pars tuberalis of the adenohypophysis is in factcharacterised in mammals by a high density of melatonin receptors(Journal of Neuroendocrinology, 1, pp. 1–4, 1989).

Protocol

-   1) Sheep pars tuberalis membranes are prepared and used as target    tissue in saturation experiments to determine the binding capacities    and affinities for 2-[¹²⁵I]-iodomelatonin.-   2) Sheep pars tuberalis membranes are used as target tissue in    competitive binding experiments using the various test compounds in    comparison with melatonin.

Each experiment is carried out in triplicate and a range of differentconcentrations is tested for each compound. The results enable thedetermination, after statistical processing, of the binding affinitiesof the compound tested.

Results

The compounds of the invention appear to have a strong affinity formelatonin receptors.

EXAMPLE C 1. Melatonin mt₁ and MT₂ Receptor Binding Study

The mt₁ or MT₂ receptor binding experiments are carried out using2-[¹²⁵I]-melatonin as reference radioligand. The radioactivity retainedis determined using a liquid scintillation counter.

Competitive binding experiments are then carried out in triplicate usingthe various test compounds. A range of different concentrations istested for each compound. The results enable the binding affinities ofthe compounds tested (IC₅₀) to be determined.

2. Study of Binding to MT₃ Melatonin Binding Sites

The MT₃ site binding experiments are carried out on hamster brainmembranes using 2-[¹²⁵I]-melatonin as reference radioligand. Themembranes are incubated for 30 minutes with the 2-[¹²⁵I]-melatonin at atemperature of 4° C. and at different concentrations of the testcompounds. After incubation, the membranes are quickly filtered and thenwashed with cold buffer using a filtration system. The radioactivityfixed is measured using a scintillation counter. The IC₅₀ values(concentration inhibiting specific binding by 50%) are calculated fromcompetition curves according to a non-linear regression model.

The IC₅₀ values found for the compounds of the invention demonstratebinding to one or other of the receptor sub-types, the values being ≦10μM.

EXAMPLE D Action of the Compounds of the Invention on the CircadianRhythms of Locomotive Activity of the Rat

The involvement of melatonin in influencing, by day/night alternation,the majority of physiological, biochemical and behavioural circadianrhythms has made it possible to establish a pharmacological model forresearch into melatoninergic ligands.

The effects of the molecules are tested on numerous parameters and, inparticular, on the circadian rhythms of locomotive activity, which are areliable indicator of the endogenous circadian clock.

In this study, the effects of such molecules on a particularexperimental model, namely the rat placed in temporal isolation(permanent darkness), is evaluated.

Experimental Protocol

One-month-old male rats are subjected, as soon as they arrive at thelaboratory, to a light cycle of 12 hours' light per 24 hours (LD 12:12).

After 2 to 3 weeks' adaptation, they are placed in cages fitted with awheel connected to a recording system, in order to detect the phases oflocomotive activity and thus monitor the nychthemeral rhythms (LD) orcircadian rhythms (DD).

As soon as the rhythms recorded show a stable pattern during the lightcycle LD 12:12, the rats are placed in permanent darkness (DD).

Two to three weeks later, when the free course (rhythm reflecting thatof the endogenous clock) is clearly established, the rats are given adaily administration of the molecule to be tested.

The observations are made by means of visualisation of the rhythms ofactivity:

-   -   influence on the rhythms of activity by the light/dark cycle,    -   disappearance of the influence on the rhythms in permanent        darkness,    -   influence on the activity by the daily administration of the        molecule; transitory or durable effect.

A software package makes it possible:

-   -   to measure the duration and intensity of the activity, the        period of the rhythm of the animals during free course and        during treatment,    -   possibly to demonstrate by spectral analysis the existence of        circadian and non-circadian (for example ultradian) components.        Results

The compounds of the invention clearly appear to allow powerful actionon the circadian rhythm via the melatoninergic system.

EXAMPLE E Light/Dark Cages Test

The compounds of the invention are tested on a behavioural model, thelight/dark cages test, which allows the anxiolytic activity of thecompounds to be demonstrated.

The apparatus consists of two polyvinyl boxes covered with Plexiglass.One of the boxes is in darkness. A lamp is placed above the other box,yielding a light intensity of approximately 4000 lux in the centre ofthe box. An opaque plastic tunnel separates the light box from the darkbox. The animals are tested individually for a session of 5 minutes. Thefloor of each box is cleaned between each session. At the start of eachtest, the mouse is placed in the tunnel, facing the dark box. The timespent by the mouse in the illuminated box and the number of passagesthrough the tunnel are recorded after the first entry into the dark box.

After administration of the compounds 30 minutes before the start of thetest, the compounds of the invention significantly increase the timespent in the illuminated cage and the number of passages through thetunnel, which demonstrates the anxiolytic activity of the compounds ofthe invention.

EXAMPLE F Activity of Compounds of the Invention on the Caudal Artery ofthe Rat

The compounds of the invention were tested in vitro on the caudal arteryof the rat. Melatoninergic receptors are present in those vessels, thusproviding a relevant pharmacological model for studying melatoninergicligand activity. The stimulation of the receptors can cause eithervasoconstriction or dilation depending on the arterial segment studied.

Protocol

One-month old rats are accustomed to a light/dark cycle of 12 h/12 hduring a period of 2 to 3 weeks.

After sacrifice, the caudal artery is isolated and maintained in ahighly oxygenated medium. The arteries are then cannulated at both ends,suspended vertically in an organ chamber in a suitable medium andperfused via their proximal end. The pressure changes in the perfusionflow enable evaluation of the vasoconstrictive or vasodilatory effect ofthe compounds.

The activity of the compounds is evaluated on segments that have beenpre-contracted by phenylephrine (1 μM). A concentration/response curveis determined non-cumulatively by the addition of a concentration of thetest compound to the pre-contracted segment. When the observed effectreaches equilibrium, the medium is changed and the preparation is leftfor 20 minutes before the addition of the same concentration ofphenylephrine and a further concentration of the test compound.

Results

The compounds of the invention significantly modify the diameter ofcaudal arteries pre-constricted by phenylephrine.

EXAMPLE G Pharmaceutical Composition: Tablets

1000 tablets each comprising 5 mg of methyl  5 g3-{2-[(cyclopropylcarbonyl)- amino]ethyl}-1-benzofuran-5-yl-carbamate(Example 75) wheat starch 20 g maize starch 20 g lactose 30 g magnesiumstearate  2 g silica  1 g hydroxypropyl cellulose  2 g

1. A compound selected from those of formula (I):R-A-R′  (I) wherein: ♦ A represents: a ring system of formula (II):

 wherein R substitutes the ring B′ and R′ substitutes either ring of thering system of formula (III), it being understood that the ring systemof formula (III) may be unsubstituted or substituted (in addition to thesubstituents R and R′) by from 1 to 6 radicals, which may be the same ordifferent, selected from R_(a), OR_(a), COR_(a), COOR_(a), OCOR_(a),OSO₂CF₃ and halogen, wherein R_(a) represents hydrogen, unsubstituted orsubstituted linear or branched (C₁–C₆)alkyl, unsubstituted orsubstituted linear or branched (C₂–C₆)alkenyl, unsubstituted orsubstituted linear or branched (C₂–C₆)alkynyl, linear or branched(C₁–C₆)polyhaloalkyl, unsubstituted or substituted (C₃–C₈)cycloalkyl,unsubstituted or substituted (C₃–C₈)cycloalkyl-(C₁–C₆)alkyl in which thealkyl group is linear or branched, unsubstituted or substituted(C₃–C₈)cycloalkenyl, unsubstituted or substituted(C₃–C₈)cycloalkenyl-(C₁–C₆)alkyl in which the alkyl group is linear orbranched, aryl, aryl-(C₁–C₆)alkyl in which the alkyl moiety is linear orbranched, aryl-(C₁–C₆)alkenyl in which the alkenyl moiety is linear orbranched, heteroaryl, heteroaryl-(C₁–C₆)alkyl in which the alkyl moietyis linear or branched, heteroaryl-(C₁–C₆)alkenyl in which the alkenylmoiety is linear or branched, unsubstituted or substituted linear orbranched (C₁–C₆)heterocycloalkyl, unsubstituted or substitutedheterocycloalkenyl, substituted or unsubstitutedheterocycloalkyl-(C₁–C₆)alkyl in which the alkyl moiety is linear orbranched, or substituted or unsubstitutedheterocycloalkenyl-(C₁–C₆)alkyl in which the alkyl moiety is linear orbranched, R represents: a group of formula (V):

wherein Q represents sulphur or oxygen, R′ represents NR′_(a)R″_(a) orOR′_(a), (wherein Wa and R″a, which may be the same or different, maytake any of the values of R_(a) and may also form, together with thenitrogen atom carrying them, a 5- to 10-membered cyclic group which maycontain, in addition to the nitrogen atom by which it is linked, fromone to three hetero atoms selected from oxygen, sulphur and nitrogen,and R′_(a) may take any of the values of R_(a) except for the hydrogenatom), a group of formula (VI):

wherein R² represents R_(a) as defined hereinbefore, R³ representsCOR′_(a), CSR′_(a), CONR′_(a)R″_(a), CSNR′_(a)R″_(a), COOR′_(a),CSOR′_(a) or S(O)_(v)R′_(a), wherein R′_(a) and R″_(a), which may be thesame or different, are as defined hereinbefore and may also form,together with the nitrogen atom carrying them, a cyclic group as definedhereinbefore, and v is 1 or 2, a group of formula (VII):

 wherein v is as defined hereinbefore and R⁴ represents NR′_(a)R″_(a),NR_(a)COR′_(a), NR_(a)CSR′_(a), NR_(a)CONR′_(a)R″_(a),NR_(a)CSNR′_(a)R″_(a) or NR_(a)COOR′_(a), wherein R_(a), R′_(a) andR″_(a) are as defined hereinbefore, or forms, together with two adjacentcarbon atoms of the cyclic structure A carrying it, a 5- to 7-memberedring of formula (VIII):

and wherein the ring of formula (VIII) may be optionally substituted byone or more radicals, which may be the same or different, selected fromR_(a), OR_(a), COR_(a), COOR_(a), OCOR_(a), NR′_(a)R″_(a),NR_(a)COR′_(a), CONR′_(a)R″_(a), cyano, oxo, SR_(a), S(O)R_(a),SO₂R_(a), CSR_(a), NR_(a)CSR′_(a), CSNR′_(a)R″_(a),NR_(a)CONR′_(a)R″_(a), NR_(a)CSNR′_(a)R″_(a) and halogen, wherein R_(a),R′_(a) and R″_(a), which may be the same or different, are as definedhereinbefore and R′_(a) and R″_(a) may also form, together with thenitrogen atom carrying them, a cyclic group as defined hereinbefore, andR′ represents a group of formula (IX):-G-R⁵  (IX) wherein G represents an alkylene chain —(CH₂)_(t)—(wherein trepresents an integer from 1 to 4, optionally substituted by one or moreradicals, which may be the same or different, selected from R_(a),OR_(a), COOR_(a), COR_(a) (in which R_(a) is as defined hereinbefore) orhalogen, and R⁵ represents

wherein Q, R_(a), R′_(a) and R″_(a) (which may be the same or different)are as defined hereinbefore, it being possible for R′_(a) and R″_(a) toform, together with the nitrogen atom carrying them, a cyclic group asdefined hereinbefore, it being understood that: “heterocycloalkyl” maybe any saturated mono- or poly-cyclic group containing from 5 to 10atoms containing from 1 to 3 hetero atoms selected from nitrogen, oxygenand sulphur, “heterocycloalkenyl” may be any non-aromatic mono- orpoly-cyclic group containing one or more unsaturations, containing from5 to 10 atoms and which may contain from 1 to 3 hetero atoms selectedfrom nitrogen, oxygen and sulphur, the term “substituted” used withrespect to “alkyl”, “alkenyl” and “alkynyl” indicates that such groupsare substituted by one or more radicals, which may be the same ordifferent, selected from hydroxy, linear or branched (C₁–C₆)alkoxy,linear or branched (C₁–C₆)alkyl, linear or branched(C₁–C₆)polyhaloalkyl, amino and halogen, the term “substituted” usedwith respect to “cycloalkyl”, “cycloalkylalkyl”, “cycloalkenyl”,“cycloalkenylalkyl”, “heterocycloalkyl”, “heterocycloalkenyl”,“hetero-cycloalkylalkyl” and “heterocycloalkenylalkyl” indicates thatthe cyclic moiety of such groups is substituted by one or more radicals,which may be the same or different, selected from hydroxy, linear orbranched (C₁–C₆)alkoxy, linear or branched (C₁–C₆)alkyl, linear orbranched (C₁–C₆)polyhaloalkyl, amino and halogen, “aryl” may be anyaromatic, mono- or poly-cyclic group containing from 6 to 22 carbonatoms, and also biphenyl, “heteroaryl“ may be any aromatic mono- orpoly-cyclic group containing from 5 to 10 atoms containing from 1 to 3hetero atoms selected from nitrogen, oxygen and sulphur, it beingpossible for the “aryl” and “heteroaryl” groups to be substituted by oneor more radicals, which may be the same or different, selected fromhydroxy, linear or branched (C₁–C₆)alkoxy, linear or branched(C₁–C₆)alkyl, linear or branched (C₁–C₆)polyhaloalkyl, cyano, carboxy,nitro, amino and halogen, it being understood that: when R⁵ representsNHCOR′_(a), then R cannot represent COOR′_(a), the compound of formula(I) cannot represent: N-{8-[(acetylamino)methyl]-2-naphthyl}-2-methylpropanamide, and 258-[(acetylamino)methyl]-N-isopropyl-2-naphthamide, or an enantiomer,diastereoisomer, or addition salt thereof with a pharmaceuticallyacceptable acid or base.
 2. A compound of claim 1, wherein A representsa ring system of formula (III) substituted in the 7-position by R and inthe 1- or 2-position by R′.
 3. A compound of claim 1, wherein Rrepresents a group of formula (V).
 4. A compound of claim 1, wherein Rrepresents a group of formula (VI).
 5. A compound of claim 1, wherein Rrepresents a group of formula (VII).
 6. A compound of claim 1, wherein Rrepresents a group of formula (V) wherein Q represents oxygen and R¹represents NR′_(a)R″_(a).
 7. A compound of claim 1, wherein R representsa group of formula (V) wherein Q represents oxygen and R¹ represents OR¹_(a).
 8. A compound of claim 1, wherein R represents a group of formula(VI) wherein R³ represents COR′_(a).
 9. A compound of claim 1, wherein Rrepresents a group of formula (VI) wherein R³ represents COOR′_(a). 10.A compound of claim 1, wherein R represents a group of formula (VII)wherein v is 2 and R⁴ represents NR′_(a)NR″_(a).
 11. A compound of claim1, wherein R′ represents G-R⁵ wherein G represents an unsubstituted orsubstituted alkylene chain —(CH₂)_(t)—wherein t is 2 or 3 and R⁵


12. A compound of formula (I) according to claim 1, wherein R′represents G-R⁵ wherein G represents an alkylene chain—(CH₂)_(t)—wherein t is 2 or 3 and R⁵ represents —NHCOR′_(a) or—CONHR′_(a).
 13. A compound of claim 1, wherein A represents a ringsystem of formula (III) substituted in the 7-position by a group offormula (V) and in the 1- or 2-position by a group of formula (IX). 14.A compound of claim 1, wherein A represents a ring system of formula(III) substituted in the 7-position by a group of formula (VI) and inthe 1- or 2-position by a group of formula (IX).
 15. A compound of claim1, wherein A represents a ring system of formula (III) substituted inthe 7-position by a group of formula (VII) and in the 1- or 2-positionby a group of formula (IX).
 16. A compound of claim 1, wherein Arepresents a ring system of formula (III), which is substituted in the7-position by a group of formula —CONR′_(a)R″_(a) and substituted in the1- or 2-position by a group of formula (IX) wherein G represents anunsubstituted or substituted chain —(CH₂)_(t)—, wherein t is 2 or 3, andR⁵ represents


17. A compound of claim 1, wherein A represents a ring system of formula(III), which is substituted in the 7-position by SO₂NR′_(a)R′_(a) andsubstituted in the 1- or 2-position by a group of formula (IX) wherein Grepresents an unsubstituted or substituted chain —(CH₂)_(t)—, wherein tis 2 or 3, and R⁵ represents


18. A compound of claim 1, wherein A represents a ring system of formula(III), which is substituted in the 7-position by a group —NHCOR′_(a) andsubstituted in the 1- or 2-position by a group of formula (IX) wherein Grepresents an unsubstituted or substituted chain —(CH₂)_(t)—, wherein tis 2 or 3, and R⁵ represents


19. A compound of claim 1, wherein A represents a ring system of formula(III) substituted in the 7-position by a group —NHCOOR′_(a) and which issubstituted in the 1- or 2-position by a group of formula (IX) wherein Grepresents an unsubstituted or substituted chain —(CH₂)_(t)—, wherein tis 2 or 3, and R⁵ represents


20. A compound of claim 1, wherein A represents a ring system of formula(III) substituted in the 7-position by a group COOR¹ _(a) and which issubstituted in the 1- or 2-position by a group of formula (IX) wherein Grepresents an unsubstituted or substituted chain —(CH2)_(t)—, wherein tis 2 or 3, and R⁵ represents


21. A compound of claim 1, wherein A represents naphthalene, which isoptionally substituted (in addition to the substituents R and R′), inthe 3-position.
 22. A compound of claim 1, wherein A representsnaphthalene, which is optionally substituted (in addition to thesubstituents R and R′) in the 3-position, substituted in the 7-positionby —NHCOR_(a), SO₂NHR_(a), COOR¹ _(a) or CONHR_(a), and substituted inthe 1-position by —(CH₂)_(t)—NHCOR′_(a) or —(CH₂)_(t)—CONHR′_(a),wherein t is 2 or
 3. 23. A compound of claim 1, wherein A representsnaphthalene, which is optionally substituted (in addition to thesubstituents R and R′) in the 3-position, substituted in the 7-positionby —NHCOOR_(a) or

wherein alk represents alkyl, and substituted in the 1-position by—(CH2)_(t)—NHCOR′_(a) or —(CH₂)_(t)—CONHR′_(a), wherein t is 2 or
 3. 24.A compound of claim 1, selected from: N-{8-[2-([2-phenylacetyl]amino)ethyl]-2-naphthyl}butanamide, N-(8-{2-[(2-bromoacetyl)amino]ethyl }-2-naphthyl)- 1-cyclohexanecarboxamide,N- {8-[2-(heptanoylamino)ethyl]-2,6-dinaphthyl}-2-butenamide, and N-{8-[2-(acetylamino)ethyl]-2-naphthyl }acetamide.
 25. A compound of claim1, selected from: N-ethyl-8-{2-[(2-phenylacetyl)amino]ethyl}-2-naphthamide,N,N-diethyl-8-{2-[2-[(cyclopropylmethyl)amino]-2-oxoethyl}-2-naphthamide,N-phenyl-8-(2-{methyl-[(propylamino)carbonyl]amino}ethyl)-2-naphthamide,N-benzyl-1-{2-[(2,2,2-trifluoroacetyl)amino]ethyl}-2-naplithamide, andN-(2-{7-[(methylamino)carbonyl]-1-naphthyl}ethyl)-2-furamide.
 26. Acompound of claim 1, selected from:N-{2-[7-(aminosulphonyl)-1-naphthyl]ethyl}acetamide,N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethyl)acetamide,N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethyl)-2-furamide,N-(2-{7-[(ethylamino)sulphonyl]-1-naphthyl}ethyl)benzamide, andN-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethylcyclopropanecarboxamide.27. A compound of claim 1, selected from: ethylN-(8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthyl)carbamate, methylN-{8-[2-(acetylamino)ethyl]-6-phenyl-2-naphthyl}carbamate, and methyl8-[2-(acetylamino)ethyl]-2-naphthyl-carbamate.
 28. A method for treatinga living animal body afflicted with a disorder of the melatoninergicsystem selected from anxiety, insomnia and fatigue due to jetlag, andmigraine, comprising the step of administering to the living animal bodyan amount of a compound of claim 1, which is effective for thealleviation of the disorder.
 29. A pharmaceutical composition comprisingas active principle an effective amount of a compound as claimed inclaim 1, together with one or more pharmaceutically acceptableexcipients or vehicles.